Opportunistic Infections Are Uncommon with Dasatinib in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP).
Authors: Al-Ameri Ali , Kantarjian Hagop , Borthakur Gautam , Bahceci Erkut , Szatrowski Ted , Damokosh Andrew , Cortes Jorge 
Published: October 2019

Abstract
Abstract 1120
Poster Board I-142

BACKGROUND
Dasatinib is a tyrosine kinase inhibitor that can achieve rapid and durable hematological, cytogenetic, and molecular responses in patients with CML-CP after resistance or intolerance to imatinib. Three years of follow-up data have been accumulated, with progression-free survival rates of 73% reported for second-line dasatinib 100 mg once daily (the currently approved dose for CML-CP). In addition to BCR-ABL, dasatinib inhibits Src family kinases (SFKs) and thereby mitigates T-cell receptor-mediated signaling. Dasatinib may have unique immunomodulatory properties. Modulation of CD8+ T-cell intracellular signal transduction, cellular proliferation, and cytokine production by dasatinib has been previously reported in vitro (Fei F. Exp Hematol. 2008;36(10):1297-308). Also, dasatinib has been shown to induce expansion of T-cells and NK cells in the clinic, an effect that was associated with achieving a complete molecular response (Mustjoki S. Leukemia. 2009;23(8):1398-405). Opportunistic infections (OI) like herpes zoster infections (HZV) have been previously reported with imatinib, albeit at a low rate (Mattiuzzi GN. Clin Cancer Res. 2003;9(3):976-80).

AIM
To determine the frequency of OI in clinical trials of dasatinib in CML-CP.

METHODS
Data from phase II CA180-013 and CA180-017, and phase III CA180-034 trial databases of 1150 CML-CP patients, collectively, were reviewed. A search for infection adverse events was conducted, and entries related to opportunistic pathogens were identified and tabulated. The follow-up time is ≥3 years for all patients in the phase III study and 2 years in the phase II studies. The median time on dasatinib treatment for patients treated with 100 mg once daily is 31 months, and for other doses is 25 months.

RESULTS
Of the 165 patients treated with dasatinib 100 mg once daily, only one grade 3–4 OI was identified (incidence <1%): a grade 3 HZV infection. In addition, there were 18 cases (11%) of grade 1–2 herpes simplex (HSV), 3 HZV, and one mycobacterial infection. Thirteen of the HSV cases were reported as not related to dasatinib treatment. Among 985 patients treated with other dosing schedules (50 mg twice daily, 70 mg twice daily, or 140 mg once daily), 7 cases (<1%) of grade 3–4 OIs were identified: 1 cytomegalovirus, 2 HSV, 1 HZV, 2 pneumocystis, and 1 unspecified fungal infection. There were 87 (9%) grade 1–2 HSV cases reported in the other dosing arms, but 62 were deemed not associated with dasatinib. There were 23 reports (2%) of grade 1–2 HZV infection with other doses, and one case of a grade 2 cytomegalovirus infection.

CONCLUSION
Our analysis indicates that OIs are rare in patients with CML-CP treated with dasatinib. Most of the infections associated with opportunistic pathogens were grade 1–2. Thus, despite in vitro data suggesting immunosuppressive properties of dasatinib, there do not seem to be adverse clinical consequences with this agent.

Disclosures
Kantarjian: Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Borthakur:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau. Bahceci:Bristol-Myers Squibb: Employment. Szatrowski:Bristol-Myers Squibb: Employment. Damokosh:Bristol-Myers Squibb: Employment. Cortes:Bristol-Myers Squibb: Research Funding.