Immunosuppression and Atypical Infections in CML Patients Treated With Dasatinib at 140 Mg Daily

Eur J Clin Invest. 2009 Dec;39(12):1098-109. doi: 10.1111/j.1365-2362.2009.02206.x. Epub 2009 Sep 9.

Abstract

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.

Patients and 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antigens, Neoplasm / drug effects
  • Antigens, Neoplasm / immunology*
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects*
  • Basophils / drug effects
  • Basophils / immunology
  • Dasatinib
  • Female
  • Flow Cytometry
  • Humans
  • Immunoglobulins / blood
  • Immunoglobulins / drug effects
  • Immunosuppressive Agents / adverse effects*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / immunology*
  • Lymphocytes / drug effects
  • Lymphocytes / immunology*
  • Male
  • Middle Aged
  • Proteome / analysis
  • Pyrimidines / administration & dosage
  • Pyrimidines / adverse effects*
  • Thiazoles / administration & dosage
  • Thiazoles / adverse effects*

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Immunoglobulins
  • Immunosuppressive Agents
  • Proteome
  • Pyrimidines
  • Thiazoles
  • Dasatinib