Phase I study of busulfan, cyclophosphamide, and timed sequential escalating doses of cytarabine followed by bone marrow transplantation.
In both animal models and human studies in leukemia, residual disease on day 8 following myelosuppressive therapy is in a proliferative phase and therefore may be sensitive to the S-phase specific drug cytarabine. Based on this concept, 17 patients with refractory or relapsed leukemia or lymphoma undergoing either autologous or allogeneic bone marrow transplantation (BMT) were treated on a Phase I protocol using high doses of busulfan (16 mg/kg, days -10, -9, -8, -7) and cyclophosphamide (120 mg/kg, days -6, -5) followed by escalating doses of a 48-h continuous infusion of cytarabine (starting dose 1000 mg/m2/48 h, days -3, -2). Ten patients received autologous transplants (two with Hodgkin's disease, seven with non-Hodgkin's lymphoma, one with chronic myelogenous leukemia (CML) in blast phase). Seven received allogeneic BMT (two with refractory acute myelocytic leukemia (AML), one with refractory acute lymphoblastic leukemia (ALL) undergoing a second BMT, one with Burkitt's-type leukemia, one with ALL in fifth relapse and two with CML in accelerated/blast phase). Two of these patients received a T cell-depleted haploidentical transplant. The maximum tolerated dose of cytarabine was 1500 mg/m2/48 h; a pulmonary syndrome including dyspnea, hypoxemia, and interstitial infiltrates which responded to aggressive diuresis was the dose limiting toxicity. Of the 10 patients who received cytarabine doses of 2000 or 2500 mg/m2/48 h, five patients developed adult respiratory distress syndrome (ARDS) with three patients requiring intubation; two recovered. Of the nine patients with lymphoma, seven responded with complete tumor clearance (CTC) with two patients tumor-free 13 and 15 months post-BMT, one remained refractory and one died too early to evaluate (TETE).(ABSTRACT TRUNCATED AT 250 WORDS)
Geller
R B
RB
Department of Medicine, University of Chicago Medical Center, Illinois 60637.
Myers
S
S
Devine
S
S
Larson
R A
RA
Williams
S F
SF
Park
C L
CL
O'Toole
K
K
Chandler
C
C
Topper
R L
RL
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000379:methods*; D002066:Busulfan / Q000008:administration & dosage*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage*; D003561:Cytarabine / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000601:surgery; D008223:Lymphoma / Q000188:drug therapy / Q000601:surgery; D008297:Male; D008875:Middle Aged
D003561:Cytarabine; D003520:Cyclophosphamide; D002066:Busulfan