Clonal Large Granular Lymphocyte (LGL) Expansion Associated with Dasatinib Therapy

• Published in: Blood 2007-11, Vol.110 (11), p.2938-2938
• Main Authors: Mustjoki, Satu, Laurinolli, Tuisku, Ekblom, Marja, Rauhala, Auvo, Sinisalo, Marjatta, Almqvist, Anders, Koivunen, Elli, Lundan, Tuija, Ebeling, Freja, Koskenvesa, Perttu, Hjorth-Hansen, Henrik, Arstila, Petteri, Stenke, Leif, Steegmann, Juan Luis, Hoglund, Martin, Simonsson, Bengt, Shah, Neil, Paquette, Ronald, Porkka, Kimmo
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V110.11.2938.2938

In addition to therapeutic efficacy in imatinib-resistant BCR-ABL positive malignancies, dasatinib may have off-target immunomodulatory effects by inhibiting kinases (e.g. SRCs, c-KIT) in immune effector cells. In a proportion of patients, dasatinib treatment is associated with non-infectious pleural effusions and panniculitis, which may reflect aberrant immune reactivity. Here we describe a marked expansion of clonal LGL lymphocytes in blood among 11 BCR-ABL positive patients on dasatinib therapy (5 CML CP, 1 CML AP, 1 CML BC, 4 Ph+ALL). All patients were previously exposed to imatinib without similar changes in lymphocyte count or morphology. The median time to LGL lymphocytosis was 2 months from the start of dasatinib (range 1–8 months). It developed abruptly, with a peak lymphocyte count of 4–20 ×109/L, and was often preceded by low-grade fever. In all evaluable cases, lymphocyte counts normalized after drug discontinuation. By immunophenotyping, 6 patients had a CD3/CD8+ cytotoxic T-cell phenotype and 4 patients had a CD56+ NK-cell phenotype. The LGL lymphocytes were BCR-ABL negative. All CD3-positive cases had a clonal rearrangement of TCR gamma/delta genes by PCR; clonality was not detected in samples prior to dasatinib therapy (n=3). In TCR beta gene repertoire assay, oligoclonal patterns were seen in selected genes. All patients with HLA data had the A2 allele (n=8). Dasatinib-related complications were common: pleural effusions and/or pulmonary infiltrates (n=8), modest CMV reactivation (n=5), severe colitis (n=5), which developed after appearance of LGL lymphocytosis. Immunophenotyping was available from 2 patients with pleural effusions: in both cases the majority of cells were CD3+CD8+ T-cells and no leukemic cells were detected. TCR gamma assay was done from one patient sample and it showed similar clonal pattern as in peripheral blood. However, despite frequent side-effects, response to dasatinib treatment was very good in all cases, including complete molecular responses in 5 advanced phase patients. Transient clonal LGL lymphocytosis has been described in few patient cases with a primary herpesvirus infection. Our patients share striking pheno/genotypic similarities with LGL leukemia, in which an antigen driven expansion of LGLs precedes the occurrence of oncogenic events. However, in our patients LGL lymphocytosis appeared to be a benign phenomenon. We postulate that by virtue of inhibition of key non-BCR-ABL kinases, dasatinib induces a