Phase I study of combined 2-chlorodeoxyadenosine and chlorambucil in chronic lymphoid leukemia and low-grade lymphoma.
OBJECTIVE
We conducted a dose-escalation study of 2-chlorodeoxyadenosine (2-CdA) added to a standard fixed dose of chlorambucil to evaluate the toxicity of the combined regimen in patients with chronic lymphocytic leukemia (CLL) and low-grade lymphoma.


METHODS
A total of 15 adults with relapsed or refractory CLL or low-grade lymphoma were to receive chlorambucil orally (30 mg/m2) every 2 weeks. Also, groups of three patients were to receive escalating doses of continuous intravenously administered 2-CdA at 1, 2, or 4 mg/m2/d for 7 days repeated at monthly intervals. All patients had pharmacokinetic studies during the first cycle of 2-CdA therapy; the results were compared with other institutional phase I studies in which comparable amounts of 2-CdA were administered by bolus infusion for 5 days.


RESULTS
The maximal-tolerated dose of 2-CdA that could be combined with chlorambucil was 2 mg/m2/d for 7 days for a maximum of two courses. At a higher dose level of 2-CdA or at the maximal-tolerated dose level given for more than two courses, severe and protracted pancytopenia, sometimes associated with life-threatening infections, was noted. Nonhematologic toxicities were limited to moderate degrees of nausea, vomiting, anorexia, and fatigue. Results of the pharmacologic studies suggested that 2-CdA clearance was independent of administration schedule and was unaffected by concomitant administration of chlorambucil.


CONCLUSIONS
These observations suggest the possibility of combining two cycles of continuous intravenously administered 2-CdA (2 mg/m2/d for 7 days) with standard doses of oral chlorambucil to test the efficacy of the combination regimen in phase II trials.
Tefferi
A
A
Division of Hematology, Mayo Clinic, Rochester, MN 55905.
Witzig
T E
TE
Reid
J M
JM
Li
C Y
CY
Ames
M M
MM
D015762:2-Chloroadenosine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002699:Chlorambucil / Q000008:administration & dosage; D003839:Deoxyadenosines / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
D003839:Deoxyadenosines; D015762:2-Chloroadenosine; D002699:Chlorambucil; C055994:2-chloro-3'-deoxyadenosine