Improved outcome in adult B-cell acute lymphoblastic leukemia.
A total of 68 adult patients with B-cell acute lymphoblastic leukemia (B-ALL) were treated in three consecutive adult multicenter ALL studies. The diagnosis of B-ALL was confirmed by L3 morphology and/or by surface immunoglobulin (Slg) expression with > 25% blast cell infiltration in the bone marrow (BM). They were characterized by male predominance (78%) and a median age of 34 years (15 to 65 y) with only 9% adolescents (15 to 20 y), but 28% elderly patients (50 to 65 y). The patients received either a conventional (N = 9) ALL treatment regimen (ALL study 01/81) or protocols adapted from childhood B-ALL with six short, intensive 5-day cycles, alternately A and B. In study B-NHL83 (N = 24) cycle A consisted of fractionated doses of cyclophosphamide 200 mg/m2 for 5 days, intermediate-dose methotrexate (IdM) 500 mg/m2 (24 hours), in addition to cytarabine (AraC), teniposide (VM26) and prednisone. Cycle B was similar except that AraC and VM26 were replaced by doxorubicin. Major changes in study B-NHL86 (N = 35) were replacement of cyclophosphamide by ifosphamide 800 mg/m2 for 5 days, an increase of IdM to high-dose, 1,500 mg/m2 (HdM) and the addition of vincristine. A cytoreductive pretreatment with cyclophosphamide 200 mg/m2, and prednisone 60 mg/m2, each for 5 days was recommended in study B-NHL83 for patients with high white blood cell (WBC) count (> 2,500/m2) or large tumor burden and was obligatory for all patients in study B-NHL86. Central nervous system (CNS) prophylaxis/treatment consisted of intrathecal methotrexate (MTX) therapy, later extended to the triple combination of MTX, AraC, and dexamethasone, and a CNS irradiation (24 Gy) after the second cycle. Compared with the ALL 01/81 study where all the patients died, results obtained with the pediatric protocols B-NHL83 and B-NHL86 were greatly improved. The complete remission (CR) rates increased from 44% to 63% and 74%, the probability of leukemia free survival (LFS) from 0% to 50% and 71% (P = .04), and the overall survival rates from 0% to 49% and 51% (P = .001). Toxicity, mostly hematotoxicity and mucositis, was severe but manageable. In both studies B-NHL83 and B-NHL86, almost all relapses occurred within 1 year. The time to relapse was different for BM, 92 days, and for isolated CNS and combined BM and CNS relapses, 190 days (P = .08). The overall CNS relapses changed from 50% to 57% and 17%, most probably attributable to the high-dose MTX and the triple intrathecal therapy. LFS in studies B-NHL83 and B-NHL86 was significantly influenced by the initial WBC count < or > 50,000/microL, LFS 71% versus 29% (P = .003) and hemoglobin value > or < 8 g/dL, LFS 67% versus 27% (P = .02). Initial CNS involvement had no adverse impact on the outcome. Elderly B-ALL patients (> 50 years) also benefited from this treatment with a CR rate of 56% and a LFS of 56%. It is concluded that this short intensive therapy with six cycles is effective in adult B-ALL. HdM and fractionated higher doses of cyclophosphamide or ifosphamide seem the two major components of treatment.
Hoelzer
D
D
Medizinische Klinik III, Universitätsklinik Frankfurt, Germany.
Ludwig
W D
WD
Thiel
E
E
Gassmann
W
W
Löffler
H
H
Fonatsch
C
C
Rieder
H
H
Heil
G
G
Heinze
B
B
Arnold
R
R
Hossfeld
D
D
Büchner
T
T
Koch
P
P
Freund
M
M
Hiddemann
W
W
Maschmeyer
G
G
Heyll
A
A
Aul
C
C
Faak
T
T
Kuse
R
R
Ittel
T H
TH
Gramatzki
M
M
Diedrich
H
H
Kolbe
K
K
Fuhr
H G
HG
Fischer
K
K
Schadeck-Gressel
C
C
Weiss
A
A
Strohscheer
I
I
Metzner
B
B
Fabry
U
U
Gökbuget
N
N
Völkers
B
B
Messerer
D
D
Uberla
K
K
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001855:Bone Marrow Diseases / Q000139:chemically induced; D016026:Bone Marrow Transplantation; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D003131:Combined Modality Therapy; D016371:Cranial Irradiation; D003520:Cyclophosphamide / Q000008:administration & dosage; D003561:Cytarabine / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D017254:Leukemic Infiltration; D008297:Male; D008578:Meninges / Q000473:pathology; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D011241:Prednisone / Q000008:administration & dosage; D012074:Remission Induction; D013280:Stomatitis / Q000139:chemically induced; D016019:Survival Analysis; D015996:Survival Rate; D013713:Teniposide / Q000008:administration & dosage; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
D003561:Cytarabine; D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; D013713:Teniposide; D007069:Ifosfamide; D011241:Prednisone; D008727:Methotrexate