Complete Remissions of Adult T-cell Leukemia with Anti-CD25 Recombinant Immunotoxin LMB-2 and Chemotherapy to Block Immunogenicity

Robert J Kreitman, Maryalice Stetler-Stevenson, Elaine S Jaffe, Kevin C Conlon, Seth M Steinberg, Wyndham Wilson, Thomas A Waldmann, Ira Pastan, Robert J Kreitman, Maryalice Stetler-Stevenson, Elaine S Jaffe, Kevin C Conlon, Seth M Steinberg, Wyndham Wilson, Thomas A Waldmann, Ira Pastan

Abstract

Purpose: 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.

Experimental design: 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.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

©2015 American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
Schema for the fludarabine and cyclophosphamide (FC)/LMB-2 trial. Cycle 1 contained only fludarabine and cyclophosphamide on days 1, 2, and 3. Cycles 2–7, which began 2 weeks after cycle 1, contained fludarabine and cyclophosphamide on days 1, 2, and 3, LMB-2 on days 3, 5 and 7, and were 3 weeks apart.
Figure 2.
Figure 2.
PFS to fludarabine and cyclophosphamide /LMB-2. In A, 6 patients with lymphoma or those receiving fludarabine and cyclophosphamide at 20 + 200 mg/m2 experienced a median PFS of 1.1 months versus 11.6 months in 10 patients with leukemia and 25 + 250 or 30 + 300 mg/m2 of fludarabine and cyclophosphamide (P < 0.0001). B, 8 patients treated with fludarabine and cyclophosphamide 25 + 250 mg/m2 and LMB-2 40 μg/kg had 10.6 month median PFS. Patient CF01 withdrew before cycle 2 and was nonevaluable for PFS.
Figure 3.
Figure 3.
Pharmacokinetics of LMB-2 in patients treated with fludarabine and cyclophosphamide/LMB-2. Peak levels are shown in A and B after the first and third doses, respectively. AUCs are shown in C and D after the first and third doses, respectively. All results are from cycle 2, the first cycle containing LMB-2.

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