A Phase I Trial of Subcutaneous (SQ) Dose-Escalated Alemtuzumab in Patients with T-Cell Lymphoproliferative Disorders (T-LPD).

BACKGROUND: T-cell lymphoproliferative disorders (T-LPD) are heterogeneous and highly chemoresistant malignancies without standard therapy. With few exceptions, cure rates with combination chemotherapy do not exceed 25–30%. We have shown that alemtuzumab (A), a humanized IgG1 targeting the CD52 antigen expressed on most human leukocytes, is cytotoxic for malignant T-cells in vitro and in vivo, regardless of p53 mutational status (

METHODS: Accrual goal: 18–21 pts with untreated (u) or relapsed (r)T-LPD, excluding untreated ALK-1-positive or primary cutaneous anaplastic large cell lymphoma. CD52 expression was not assessed. Other exclusion criteria: pregnancy, HIV+, HCV+, or HBV+. Primary objective: A maximal tolerated dose (MTD). DLT defined as grade (G) ≥ 3 (or non-reversible grade 2) non-hematologic toxicity or G4 neutropenia or thrombocytopenia requiring >7 day delays in therapy for > 3 times. All pts received single agent SQ A loading (3, 10, 30 mg) over 5 days followed by one SQ A dose with each cycle of CHOP every 21 days for a total of 8 cycles. A dose levels: 3, 10, 20, 30 mg. All pts received valacyclovir, trimethoprim-sulfamethoxasole prophylaxis and G-CSF. Erythropoietin was given according to published guidelines.

RESULTS: 18 pts were enrolled (uPTCL=11, uT-PLL=2, rCTCL=3, uSezary Syndrome=2). Enrollment according to dose level: 3mg = 6 pts; 10mg = 3 pts; 20 mg = 6 pts; 30 mg = 3 pts. Median age: 62 years. All pts completed single agent SQ A loading on time with minimal local reactions. Ten pts completed all planned therapy. Six pts did not complete therapy: 2 rCTCL=stable disease, 1 uPTCL=poor compliance, 2 PTCL=pt witdrew, 1 uT-PLL=progression. Two pts (30 mg dose level) are receiving therapy.

Toxicity: G4 febrile neutropenia=1; G3 fatigue=2, G3 anemia=2, G3 dyspnea=1, G3 emesis=2, G3 CMV infection=1. Cohort 1 was expanded due to asymptomatic CMV reactivation requiring hospitalization for thrice daily foscarnet. Subsequent asymptomatic CMV reactivations (N=4) were treated with oral valganciclovir until clearance. No symptomatic CMV reactivation or other viral or fungal infections were seen. Out of 107 cycles of A/CHOP given, only 3 had to be delayed. Four pts (1 PTCL, 1 T-PLL and 2 Sezary) are in continuous clinical and molecular (PCR) complete response at 36, 28, 18 and 12 months respectively.

CONCLUSIONS: SQ A was safely administerd up to 20 mg with each cycle of CHOP chemotherapy and growth factor support without excessive myelosuppression or infectious AEs. Treatment at 30 mg dose level is in progress. Asymptomatic CMV reactivation can be managed with oral valganciclovir without discontinuation of therapy. Durable responses have been seen, including molecular clearance of the malignant T-cell clone.