Immunosuppression and atypical infections in CML patients treated with dasatinib at 140 mg daily.
BACKGROUND
The multikinase inhibitor dasatinib exerts growth-inhibitory effects in patients with imatinib-resistant chronic myeloid leukaemia (CML). In first clinical trials, side effects of dasatinib, 140 mg daily, were reported to be mild and tolerable.


METHODS
We examined the side effect profile in 16 patients with imatinib-resistant CML who received 140 mg dasatinib daily in our center.


RESULTS
Dasatinib produced substantial and sometimes severe or even life-threatening side effects with > or = 10% body weight loss (6/16 patients), pleural effusions grade II or higher (12/16) and infectious complications (12/16), including atypical infections not seen in imatinib-treated patients. One patient developed Epstein-Barr-Virus-positive mucosal leucoplakia, one died from pneumonia caused by pneumocystis carinii and three patients developed a skin-cancer. Most events were recorded within the first 2 years of therapy, only skin tumours developed after the second year. In ex vivo experiments performed in dasatinib-treated patients, transient suppression of IgE-dependent activation of blood basophils and TcR-dependent activation of T-lymphocytes was found. Moreover, in drug-binding studies, dasatinib was found to bind to several key kinase-targets of the immune system including Lyn and Btk, in mast cell, basophil, B-cell and T-cell lines.


CONCLUSIONS
Dasatinib acts not only anti-neoplastic in CML but may also act as an immunosuppressive agent when applied at 140 mg daily, and produces frequent pleural effusions and weight loss in advanced CML.
Sillaber
C
C
Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria.
Herrmann
H
H
Bennett
K
K
Rix
U
U
Baumgartner
C
C
Böhm
A
A
Herndlhofer
S
S
Tschachler
E
E
Superti-Furga
G
G
Jäger
U
U
Valent
P
P
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000187:drug effects / Q000276:immunology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001491:Basophils / Q000187:drug effects / Q000276:immunology; D000069439:Dasatinib; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007136:Immunoglobulins / Q000097:blood / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000276:immunology*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020543:Proteome / Q000032:analysis; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects*; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects*
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D007136:Immunoglobulins; D007166:Immunosuppressive Agents; D020543:Proteome; D011743:Pyrimidines; D013844:Thiazoles; D000069439:Dasatinib