Complete Remissions of Adult T-cell Leukemia with Anti-CD25 Recombinant Immunotoxin LMB-2 and Chemotherapy to Block Immunogenicity.
OBJECTIVE
Adult T-cell leukemia (ATL) is usually CD25(+) and rapidly fatal. Anti-CD25 recombinant immunotoxin LMB-2 had phase I activity limited by immunogenicity and rapid growth. To prevent antidrug antibodies and leukemic progression between cycles, a phase II trial was performed with LMB-2 after cyclophosphamide and fludarabine.


METHODS
ATL patients received cyclophosphamide and fludarabine days 1 to 3 and 2 weeks later began up to 6 cycles at 3-week intervals of cyclophosphamide and fludarabine days 1 to 3 followed by LMB-2 30-40 μg/kg i.v. days 3, 5, and 7. Three different dose levels of cyclophosphamide and fludarabine were used, 20+200 (n = 3), 25+250 (n = 12), and 30+300 mg/m(2) (n = 2).


RESULTS
Of 17 patients enrolled and treated with fludarabine and cyclophosphamide for cycle-1, 15 received subsequent cycle(s) containing LMB-2 and were therefore evaluable for response. Lack of antibody formation permitted retreatment in most patients. Of 10 evaluable leukemic patients receiving 25+250 or 30+300 mg/m(2) of fludarabine and cyclophosphamide, 6 (60%) achieved complete remission (CR) and 2 (20%) partial remission (PR), and all 5 with >25% leukemic cells achieved CR. No responses were achieved in 5 with lymphomatous ATL or lower fludarabine and cyclophosphamide doses. Median CR duration for the 6 CRs was 40 weeks. One is without detectable ATL at 47 months. Toxicity was mostly attributable to fludarabine and cyclophosphamide. Capillary leak from LMB-2 was non-dose limiting. One patient in CR died of a preexisting infection.


CONCLUSIONS
LMB-2, administered with fludarabine and cyclophosphamide to prevent antidrug antibodies and rapid intercycle progression, is highly effective in achieving CR in leukemia ATL. Fludarabine and cyclophosphamide dose/schedule is important for safety and efficacy in this high-risk population.
Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland. kreitmar@mail.nih.gov.
Robert J
RJ
Kreitman
Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland.
Maryalice
M
Stetler-Stevenson
Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland.
Elaine S
ES
Jaffe
Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, Maryland.
Kevin C
KC
Conlon
Biostatistics and Data Management Section, Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
Seth M
SM
Steinberg
Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, Maryland.
Wyndham
W
Wilson
Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, Maryland.
Thomas A
TA
Waldmann
Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland.
Ira
I
Pastan
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000917:Antibody Formation / Q000187:drug effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005098:Exotoxins / Q000627:therapeutic use; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D012074:Remission Induction / Q000379:methods; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
D000911:Antibodies, Monoclonal; C077707:B3(Fv)-PE38KDEL recombinant immunotoxin; D005098:Exotoxins; C508017:IL2RA protein, human; D000922:Immunotoxins; D053645:Interleukin-2 Receptor alpha Subunit; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine