Efficacy of combining dasatinib and FLAG-IDA for patients with chronic myeloid leukemia in blastic transformation

The prognosis of patients with chronic myeloid leukemia (CML) has improved considerably over the last ten years with the introduction of ABL tyrosine kinase inhibitors (TKI) into clinical practice. TKIs induce complete cytogenetic remissions (CCyR) in 10–45% of patients who are treated with these drugs in advanced phase with minimal toxicity; unfortunately, these remissions are typically short lasting.1,2 Dasatinib alone induces CCyR in 20–40% of patients.2,3 However, the majority relapse within one year and the median survival is eight months.2 Conventional chemotherapy regimens, such as FLAG-IDA, can induce CCyR in 30–40% of patients who have progressed to blastic phase, but again most patients relapse within six months and survival is poor.4 A logical approach might be to combine both strategies in order to improve the outcome. The proposed schedule of combination TKI and chemotherapy is supported by two clinical observations: i) a number of chemotherapeutic agents commonly used in the management of blastic phase CML have been shown to have synergism with a TKI (e.g. cytarabine);5–8 and ii) TKIs have been used successfully in combination with conventional chemotherapy for the treatment of Ph ALL.9 We report our experience of dasatinib/FLAG-IDA chemotherapy in 4 CML patients who progressed to blastic phase while on imatinib.

Table 1.Patients’ characteristics and responses.

The 4 patients received first-line imatinib for 11, 7, 26 and 10 months, respectively, before progressing to blastic phase. Table 1 shows patients’ characteristics. Patients received two courses of FLAG-IDA (G-CSF 300 μg/day sc Days 0 to 6, fludarabine 30mg/m iv Days 1 to 5, cytarabine 2g/m iv Days 1 to 5, and idarubicin 12 mg/m iv Days 1 to 3) together with dasatinib 100 mg daily. Dasatinib was administered continuously from Day 0 of the first course of chemotherapy. The combination was fairly well tolerated (Table 1) and all patients recovered a neutrophil count over 1×10/L within 30 days of the start of combination therapy.

After the first course of chemotherapy, all patients achieved morphological remission (95CI 40–100%); one achieved major cytogenetic response and the remaining 3 achieved both CCyR and major molecular response (MMR). The patients who failed to achieve CCyR after the first course of chemotherapy achieved CCyR and MMR after the second cycle. Currently all 4 patients are alive; Patients 1, 2 and 3 have undergone allogeneic stem cell transplantation (continuing in remission 3, 12 and 13 months post transplant) and patient 4 is scheduled to do so shortly. Dasatinib was reintroduced on Day +30 after transplant in all 3 patients with good tolerance. We have shown that dasatinib can be safely combined with conventional chemotherapy, and although this approach should be tested in a larger number of patients, the combination seems to induce deep remissions in patients with CML in blastic phase, allowing for further therapeutic strategies to enable a continuing response.

Footnotes

• The information provided by the authors about contributions from persons listed as authors and in acknowledgments is available with the full text of this paper at www.haematologica.org.
• Financial and other disclosures provided by the authors using the ICMJE (www.icmje.org) Uniform Format for Disclosure of Competing Interests are also available at www.haematologica.org.