Durable hematologic complete response and suppression of HTLV-1 viral load following alemtuzumab in zidovudine/IFN-{alpha}-refractory adult T-cell leukemia

Abstract

Adult T-cell leukemia (ATL) is a highly chemoresistant and usually fatal T-cell malignancy due to the human T-cell lymphotropic virus-1 (HTLV-1). After chemotherapy failure, antiretrovirals and interferon-alpha (IFN-alpha) produce brief responses followed by progression and death. More effective agents and new approaches to detect and treat minimal residual disease are needed. ATL cells express CD52, the target of the antibody alemtuzumab, which is active in a preclinical model of ATL and is cytotoxic for p53-deficient cells. A patient with refractory chronic ATL in transformation achieved longer than a 1-year complete hematologic response following 12 weeks of outpatient subcutaneous alemtuzumab. Persistent suppression of HTLV-1 viral load, even at recovery of T cells, after alemtuzumab and efficient in vitro complement-mediated cytotoxicity of primary ATL cells with mutated TP53 were observed. The unprecedented response and the profound suppression of HTLV-1 viral load observed in this patient suggest that further clinical investigation of alemtuzumab in ATL is warranted.

Figure 1.

Reduction of CD4⁺ T cells and HTLV-1 viral load following denileukin diftitox and alemtuzumab. Results are depicted as HTLV-1 copies per microgram of DNA relative to time (♦). The number of CD4⁺ cells per cubic millimeter was determined by FACS analysis using antihuman CD4 antibody. Results are depicted as CD4⁺ cells per cubic millimeter relative to time (•). Denileukin diftitox and alemtuzumab treatment periods are indicated as bars above the line graphs.

Figure 2.

Alemtuzumab-induced death in human ATL cells in vitro. Primary ATL cells from the patient described in this report (ATL-1) (▪) and from a previous patient with acute ATL (ATL-2) (□) were incubated for 4 hours in media with alemtuzumab and anti-Fc IgG (both 10 μg/mL) (direct apoptosis), alemtuzumab (10 μg/mL) with PBMCs at an effector-target ratio of 25:1 (ADCC), or alemtuzumab (10 μg/mL) in media with 30% human serum (CDC). Cell death was determined by propidum iodide staining with FACS analysis for direct apoptosis and CDC, or a chromium-51 release assay for ADCC. ATL-2 cells carried a mutated TP53 gene. Experiments were done in triplicate, and results are expressed as average. Bar height reflects the average percentage of dead cells as compared with untreated control values.