Lestaurtinib FLT3 Inhibitory Activity Is Modulated by Concomitant Azole Therapy and May Influence Relapse Risk.

Abstract 789

Activating mutations of the receptor tyrosine kinase FLT3 occur in approximately one-third of adults with AML and are associated with adverse prognosis. The kinase inhibitor lestaurtinib (CEP701) has demonstrated clinical activity when used as monotherapy in both relapsed/refractory FLT3-AML (1) and newly-diagnosed older patients unfit for chemotherapy (2). In these studies, sustained plasma drug activity sufficient to inhibit FLT3 by >85% was found to be a prerequisite for clinical response. Following clear demonstration of in vitro synergy with chemotherapy (3), the clinical efficacy of lestaurtinib given sequentially following chemotherapy is being evaluated.

As part of an ongoing randomised assessment of lestaurtinib (MRC AML15 and 17 trials) 88 patients (median age 47 years [range 16-66], 66 FLT3-ITD, 22 FLT3-TKD point mutation) received lestaurtinib for up to 28 days following each of 4 courses of chemotherapy. Initially patients were dosed at 80mg bid. Unlike all other trials of this agent in AML, concomitant use of azole anti-fungal drugs, which have CYP3A4 inhibitory activity, was permitted. The initial experience demonstrated that patients on azoles tolerated lestaurtinib poorly due to gastrointestinal toxicity, so azole treated patients were able to dose reduce to 40-60mg bid which has been well tolerated.

FLT3 plasma inhibitory activity (PIA) was monitored on day 14 of each lestaurtinib course. 101 timepoints were available in 50 patients. FLT3 PIA of >85% and >95% was seen, respectively, at 82% and 49% of measured timepoints. 77 of 83 evaluable patients (93%) achieved complete remission. Only 1 of the 50 patients providing adequate plasma samples failed to enter CR: this patient also failed to achieve 80% FLT3 PIA. 26(34%) of these patients have relapsed at a median follow-up of 12 months. Analysis of relapse, adjusted for known prognostic factors of age, cytogenetics and white cell count, shows the most significant independent predictor of relapse to be >95% FLT3 PIA at one or more timepoints (4/16 vs 11/31, hazard ratio 0.27, p=0.04); >95% inhibition at 2 or more timepoints was also significant (1/7 vs 6/21, p=0.02) but patient numbers were smaller in this comparison.

Better sustained FLT3 inhibitory activity was found in patients receiving concomitant azoles: FLT3 PIA of >85% and >95% seen, respectively, at 91% and 55% of 55 timepoints in azole-treated patients compared with 67% and 39% of 46 timepoints in patients not receiving azole prophylaxis (p=0.003 for >85% PIA, p=0.12 for >95% PIA). This relationship was particularly evident in patients receiving lestaurtinib at reduced doses (40-60mg) where FLT3 PIA of >85% and >95% was seen, respectively, in 40% and 0% of 10 timepoints in ‘non-azole' cases compared to 89% and 46% of 35 timepoints in those on azoles (p=0.001 and 0.008).

These results emphasise the continuing importance of correlative laboratory studies in assessing the clinical effects of FLT3 inhibition in AML. Concomitant azoles appear to significantly influence the FLT3 inhibitory activity of lestaurtinib and can be combined safely following dose modification. The emerging relationship between sustained FLT3 PIA and alteration of relapse risk will continue to be assessed in the ongoing NCRI AML17 Trial.

(1) Smith BD et al. Blood 2004; 103: 3669-3676. (2) Knapper S et al Blood 2006; 108: 3262-3270. (3) Levis M et al. Blood 2004; 104: 1145-1150.