Dasatinib for Imatinib- resistant CML: Two Years Later

Abstract & Commentary

By William B. Ershler, MD

Synopsis: In a two-year follow-up of an initial report of a multisite, randomized trial comparing dasatinib 70 mg twice daily with imatinib 400 mg twice daily for patients who had proven resistant to lower doses of imatinib (400 mg or 600 mg daily), the improved cytogenetic responses initially reported appear durable, and the estimated progression-free survival was better for the dasatinib-treated patients.

Source: Kantarjian H, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily. Two-year follow-up of a randomized phase 2 study (START-R). Cancer. 2009;115:4136-4147.

Prior to the approval of dasatinib, and then later nilotinib, the treatment options for imatinib-resistant patients with chronic myelogenous leukemia (CML) included dose escalation of imatinib to 800 mg/m2; there was also some indication that this was effective in some patients.1,2 As dasatinib was developed, it was apparent that its potency in vitro was 325-fold greater than imatinib at inhibiting unmutated BCR-ABL,3 and this, coupled with its activity against imatinib-resistant mutations in vitro,4 provided rationale for its investigation in patients with imatinib resistance. Indeed, there are now several published reports of the effectiveness of dasatinib in this situation,5-7 including an earlier report of the current clinical trial.8 This was a an international multisite, randomized study in which 150 adult patients with chronic phase CML (CP-CML), who were resistant to imatinib at doses of 400-600 mg daily, were enrolled within one calendar year (2005) and treated with either dasatinib 70 mg twice daily (n = 101) or imatinib 400 mg twice daily (n = 49). The primary endpoint of this study was the estimated major cytogenetic response rate (MCyR) at 12 weeks, and it was found that dasatinib treatment resulted in higher MCyR (52%) than high-dose imatinib (33%) (p = 0.023). The study was designed so that patients could cross over to the alternate treatment arm for disease progression or intolerable toxicity. The current report details responses after two years of follow-up. Dasatinib-treated patients continued to demonstrate higher rates of complete hematologic response (93% vs. 82%; p = 0.034), major cytogenetic response (MCyR) (53% vs. 33%; p = 0.017), and complete cytogenetic response (44% vs. 18%; p = 0.0025). At 18 months, the MCyR was maintained in 90% of patients on the dasatinib arm and in 74% of patients on the high-dose imatinib arm. Major molecular response rates also were more frequent with dasatinib than with high-dose imatinib (29% vs. 12%; p = .028). The estimated progression-free survival also favored dasatinib (unstratified log-rank test; p = .0012).

Commentary

Thus, the two-year follow-up data demonstrate the efficacy and safety of dasatinib administration for imatinib-resistant CP-CML patients. Dasatinib also demonstrated a positive effect regardless of the prior imatinib dose received by patients. Furthermore, it is notable that dasatinib resulted in complete cytogenetic response (CCyR) in 44% of patients because the experience with imatinib treatment suggests that such a milestone is associated with a low risk of disease progression and improved survival.9

The dose of dasatinib (70 mg, twice daily) might be more than is needed. Recently, a phase III, dose-optimization study, with a median treatment duration of eight months in similar patients (i.e., chronic phase CML with imatinib intolerance or resistance),10 demonstrated that 100 mg once daily and 70 mg twice daily produced similar levels of efficacy, but the single 100 mg dose was associated with a lower incidence of cytopenias and a significantly lower incidence of grade 3/4 thrombocytopenia and pleural effusion. In fact, reading the details of the current report, because of the planned dose modifications, the average median dose of dasatinib for those initially prescribed at 70 mg twice daily (140 mg) was approximately 100 mg. Thus, it is apparent that the 100 mg, once-daily dose has a better risk/benefit ratio and should be considered the optimal choice when using this drug in this situation.

References

1. Kantarjian HM, et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood. 2003;101:473-475.

2. Marin D, et al. Transient benefit only from increasing the imatinib dose in CML patients who do not achieve complete cytogenetic remissions on conventional doses. Blood. 2003;102::2702-2703.

3. O'Hare T, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005;65:4500-4505.

4. Shah NP, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;305:399-401.

5. Hochhaus A, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008;22:1200-1206.

6. Hochhaus A, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109:2303-2309.

7. Talpaz M, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531-2541.

8. Kantarjian H, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007;109:5143-5150.

9. Druker BJ, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.

10. Shah NP, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol. 2008;26:3204-3212.