NKT cell-infiltrating aseptic meningitis on the central nervous system in Philadelphia chromosome-positive acute lymphoblastic leukemia treated with dasatinib.

Dear Editor, Among the TKIs, dasatinib is an ABL kinase inhibitor characterized by strong binding affinity to the ABL kinase domain [1]. Dasatinib is different from the other resting TKIs as a unique immunological activator. It is thought that dasatinib exerts an immunomodulatory effect to enhance the innate immune system involving natural killer (NK), natural killer T (NKT) cells, and large granular lymphocytes (LGL) under certain circumstances [2, 3]. A 53-year-old female was transferred to our institute due to febrile leukocytosis. She was diagnosed as having Ph ALL and received induction chemotherapy consisting of cyclophosphamide, daunorubicin, vincristine, and prednisolone, followed by imatinib 600 mg/day (days 8–63). She achieved complete remission after the induction chemotherapy, as her bone marrow aspiration showed molecular remission confirmed by the evaluation of BCR-ABL messenger RNA (mRNA) (<1.0×10). We performed a first consolidation chemotherapy consisting of high-dose methotrexate 1 g/m and cytarabine 2 g/m/day for 2 days, followed by dasatinib 140 mg/day (days 29–56). The patient maintained complete remission with undetectablemolecular evidence of BCR-ABL oncogene product. We initiated a second consolidation, with the same regimen as the first consolidation, and on day 34, she felt hypersensitivity on both palms. The patient’s neurological examination showed no abnormal findings included. A cranial MRI revealed no intracranial lesion explaining her neurological symptoms, while a spinal tap revealed elevatedmononuclear cell counts. The infiltrating cells consisted of granulocytes (CD3433) 15 %, B cells (CD19) 0.6 %, T cells (CD3) 98.2 %, NK cells (CD356) 1.21 %, and NKT cells (CD356) 3.0 % (Fig. 1a). Some infiltrating cells revealed LGL morphology (Fig. 1b). Cultured cerebrospinal fluid (CSF) showed no bacterial organisms or acid-fast bacillus. Molecular biological methods using CSF, a fluorescence in situ hybridization (FISH) analysis, and mRNA for BCR-ABL did not uncover findings of leukemic involvement of the CNS and bone marrow. Soon after the discontinuation of dasatinib, the patient’s neurological symptoms were ameliorated, and the infiltrating mononuclear cells disappeared completely. A high proportion of NK cells (LGLs) and NKT cells is thought to be an immunological reaction involved in dasatinib-induced immunomodulation, which has been observed several times in various clinical situations [3, 4]. The cell surface antigen analysis we performed by a flow cytometry technique revealed the NK and NKT cell infiltration, and notably, the NKT cell composition was concentrated in the CSF more than in the peripheral blood (at most 0.01 %). Almost all of the infiltrating cell population was T cells, but a minor population of NK and NKT cells was present, which was similar to the case presenting pleural effusion during dasatinib therapy.We did not determine the antigen specificity of Tcells. Even so, an accumulation of NKTcells in the CSF is an unusual event, and this case appeared to be “immunogenic” aseptic meningitis. Although the mechanisms by which activated NKTcells confer disease protection remain to be examined in future studies, those immunomodulatory properties of NKT cells suggested in the present patient may be useful for the development of immunotherapies against hematological malignancies other than Ph ALL that involve the CNS. O. Imataki (*) :A. Matsuoka :M. Uemura Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan e-mail: oima@med.kagawa-u.ac.jp