L-Asparaginase Monotherapy for T- and NK-Cell Type of Chronic Active Epstein-Barr Virus Infection in Adults: A Pilot Study

Abstract 4953

Chronic active Epstein-Barr virus infection (CAEBV) is a rare and fatal disorder. In Japan and East Asia, most CAEBV patients are the T- or NK-cell-infected type and they have been resistant to the current chemotherapies.

L-asparaginase (L-asp) is a reagent that has a well-known effect on extranodal NK-/T-cell lymphoma nasal type (ENKL) even as a single reagent. CAEBV is one of the EBV-positive T- or NK-cell lymphoproliferative diseases (EBV-T/NK-LPD) as is ENKL. In addition, L-asp is not influenced by P-glycoprotein, which is expressed in EBV-infected T-or NK-cells of CAEBV (our unpublished data). In this pilot study, therefore, we investigated its effects on T- and NK-cell type of CAEBV.

Adult patients of CAEBV without severe organ dysfunction were enrolled. CAEBV was diagnosed according to the following criteria: persistent infectious mononucleosis-like symptoms, elevation (>1 X10² copies/μg DNA) in peripheral blood EBV-DNA titer (pEBV-DNA), and the presence of EBV-infected T- or NK-cells. To detect infected cells, we isolated peripheral mononuclear cells and divided them into CD19-, CD4-, CD8-, or CD56-positive fractions using antibody-conjugated magnetic beads. EBV-DNA of each fraction was quantified using a real-time quantitative polymerase chain reaction (PCR) assay. The treatment protocol involved 7 administrations of 6000 U/m² L-asp every other day. The response was defined by the decrease of pEBV-DNA 1 month after treatment completion. We also performed quantification of asparagine synthetase (AS) in EBV-infected cells of the patients.

The results were summarized in the table. Between February 2010 and September 2010, 5 females were enrolled. Two patients were previously treated with the regimen comprising cyclosporine A, prednisolone, and VP16. One patient had EBV-positive cell infiltration of muscles with an elevation of LDH and CK. The mean titer of EBV-DNA in peripheral whole blood was 1.2 × 10⁵ copies/μg DNA.

Three patients completed the treatment. pEBV-DNA decreased in 1 patient with a reduction rate of 0.09 with improvement of clinical symptoms, but increased 2.7-fold in another patient and remained almost unchanged in the other. The response rate was 20% (1/5). Of the patients whose treatment was discontinued, one showed progression of the nasal lesion with pEBV increasing 1.5-fold, and the other had a dystonic attack on day 11, and the 2 remaining administrations were stopped although the muscle lesions were improved.

Several adverse events (AE) were detected, including liver dysfunction (grade 2 and 3) in 2 patients and neutropenia (grade 3) in 1 patient. One patient had a dystonic attack as described earlier. The brain MRI showed no lesion in the central nervous system that could have caused this attack. Because the patient had been diagnosed with dystonia before she developed CAEBV, the attack was considered not to be directly attributable to L-asp.

We examined AS mRNA levels in the EBV-infected cells. mRNA level was low in the patient who achieved pEBV-DNA decrease. As shown in the table, however, we could not find a significant relationship between the effect and AS levels.

In general, the effect of L-asp on CAEBV was limited and the rate of AE was high. However, L-asp may have responses in some patients. CAEBV has a diverse phenotype of clinico-pathological findings and associated symptoms. Treatment for CAEBV needs to be planned and evaluated according to the subtype of the disease.

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