Src family kinases (SFKs), in particular Lyn kinase, play a critical role in mediating GM-CSF and G-CSF response in myeloid leukemic cell proliferation. Lyn kinase is constitutively active in AML blasts and MDS megakaryocyte progenitors, and inhibition of Lyn suppresses leukemic cell growth in vitro (Ozawa Y, et. al. Leuk Res 2008). Given dasatinib's broad spectrum of kinase inhibition, we hypothesized that dasatinib treatment could limit blast proliferation in patients with high risk MDS.
This was a single-center, open-label, 2-stage phase II pilot study of dasatinib in patients with Int-2 or High risk MDS according to International Prognostic Scoring System (IPSS) score. All WHO subtypes of MDS, CMML, or MDS/MPD were allowed. Patients with AML with Multilineage Dysplasia (MDS/AML) with <30% blasts (RAEB-t) who either declined or were deemed unfit for induction chemotherapy were also eligible. Exclusion criteria were WBC >50,000 off hydroxyurea, another malignancy requiring radiation or chemotherapy within the past 3 years, or concurrent therapy for MDS or AML. The primary objectives were to estimate the response rates utilizing international working group criteria (IWG 2006). Secondary objectives were to assess time to progression, median duration of response, and to assess the relationship between response and target phosphorylation of src-Tyr416. All patients received a daily dose of oral dasatinib 100 mg daily. All patients were followed for 16 weeks from the first dose. Dose escalation to 150 mg per day was permitted for patients who did not achieve at least a partial response and who were tolerating treatment. Responding patients continued dasatinib treatment for up to 48 weeks in the absence of treatment failure, disease progression, limiting toxicity, or death.
Between March 7, 2008 and July 15, 2009, 18 patients were treated at the Moffitt Cancer Center. Median age was 73.5 years (range 60–84), 10 (55%) were male, median bone marrow blast percentage was 13.5%, and all patients had received prior therapy with hypomethylating agents (HMAs). By WHO classification, 2 patients (11%) had RAEB-1, 11 (61%) had RAEB-2, 2 had AML (11%), and 3 (17%) had CMML. There were 3 responses (17%), all of which were marrow CRs without hematologic improvement. Four patients (22%) had stable disease and 10 patients (59%) experienced disease progression. One patient stopped treatment after one week due to cholecystitis and elected for hospice. Fifteen of the 18 patients discontinued therapy due to lack of hematologic response or disease progression, 2 due to adverse events, and one patient received an allogeneic stem cell transplant. Eight of the 16 patients (50%) with MDS or CMML progressed to AML with a median time to progression of 4.4 months [95% CI 0.3–8.5 months]. Kaplan-Meier estimate of median overall survival was 7.6 months [95% CI 2.6–12.5 months] (Figure 1), with an estimated 1 year survival of 38%. The 7 patients that achieved at least stable disease had longer survival (28.5 months, 95% CI 0.0–60.9) than the 11 patients with disease progression or failure (4.0 months, 95% CI 1.8–6.3). The most common grade 3 or 4 toxicities were fatigue, infection, anemia, and thrombocytopenia. Laboratory studies evaluating src-Tyr416 phosphorylation are currently under review.
Dasatinib was found to have limited activity in patient higher-risk myelodysplastic syndromes that failed HMAs, but with acceptable toxicity. Further studies should focus on development of predictive markers to guide selection of patients most likely to benefit.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.