Page 100 - 2021_06-Haematologica-web

M. Swaminathan et al.
A
Figure 3. Survival of patients with FLT3- ITD+ relapsed/refractory acute myeloid leukemia given first salvage treatment with quizartinib in combination with azacitidine or low-dose cytarabine. (A) Overall survival. (B) Relapse-free sur- vival. Quiz: quizartinib; AZA: azacitidine; LDAC: low-dose cytarabine; mo: months.
B
between quizartinib and AZA. Similarly, in phase II studies, quizartinib monotherapy showed some activity in patients with FLT3-WT AML with a CRc rate of 32%.29 Our study included only three patients with FLT3-WT, who received quizartinib-based combinations as first salvage treatment but had no response. Because of the paucity of patients, no conclusion could be made on the clinical activity of quizar- tinib in combination with AZA or LDAC in patients with FLT3-WT AML. However, based on the reported CRc rate of 32% with quizartinib monotherapy,14 this approach deserves further investigation in this subset of patients.
Prior studies found that point mutations and gatekeeper mutations (F691L) were the common resistant mutations that were acquired following quizartinib therapy.30-32 In this series, FLT3-D835 was acquired at the time of pro- gression in 27% of patients. This is equivalent to what we had reported previously with single-agent FLT3 inhibitors, mostly sorafenib.33 Other mutations encountered at the time of progression included EZH2 and CREBBP muta- tions. However, the mutation analysis was somewhat lim- ited in this study, since mutation data at the time of treat- ment discontinuation were available for only 41/70 (59%) patients (Online Supplementary Figure S3). Similarly, after treatment with gilteritinib, resistance is associated with
the emergence of additional mutations, frequently RAS. This may represent a selection of clones, often pre-exist- ing, which emerge as clones with sensitive FLT3 muta- tions are suppressed by potent FLT3 inhibitors. This sug- gests that combination therapy would be required to fur- ther improve the outcome of patients treated with FLT3 inhibitors. The higher rate of response and more durable responses seen in the present study compared to what has been reported with quizartinib monotherapy are encour- aging and merit further investigation.
Like quizartinib monotherapy, quizartinib at a dose of 60 mg in combination with AZA or LDAC was very well tolerated. QTc prolongation was infrequent with only two patients developing grade 3 prolongation and requiring a decrease in quizartinib dose to 30 mg. Overall, therapy was well tolerated by our patients in both the cohorts.
As previously reported, a higher FLT3-ITD allelic ratio was found to correlate with the rate of CRc in patients receiving frontline therapy, although the optimal cut point for the ratio was at 0.5 rather than the 0.7 that had been previously proposed. However, no such correlation could be identified for survival. There were no significant corre- lations between allelic ratio and responses or survival in the salvage cohort (Online Supplementary Figure S6 and
2128
haematologica | 2021; 106(8)