Evaluating Midostaurin Plus Intensive Chemotherapy in Older Patients With AML

Midostaurin plus intensive chemotherapy, followed by allogeneic hematopoietic cell transplantation (alloHCT) and single-agent midostaurin maintenance therapy, was improved survival outcomes in patients with newly diagnosed, FLT3-ITD-positive acute myeloid leukemia (AML), though the authors observed a high rate of cardiac toxicities in older patients during treatment. The results of the phase II study, which were published in Blood, also suggest that only a small subset of patients could tolerate midostaurin as maintenance therapy.

“The role of alloHCT in first complete remission (CR) to overcome the negative impact of FLT3-ITD … on survival remains controversial,” wrote Richard F. Schlenk, MD, from the University Hospital of Ulm in Germany, and co-authors. But, according to their findings, “midostaurin significantly improved event-free survival [EFS; compared with historical controls] and alloHCT in first remission after midostaurin and chemotherapy is feasible and highly effective, irrespective of age.”

This hypothesis-generating trial enrolled adult patients (age range = 18-70 years) with newly diagnosed FLT3-ITD-positive AML. A total of 284 patients (median age = 54.1 years; range = 18-70 years) started induction therapy, which consisted of one cycle of 7+3 cytarabine and daunorubicin with twice-daily midostaurin 50 mg starting on day eight until 48 hours before the start of the next chemotherapy cycle. Of the total, 279 patients (98%) received at least one dose of midostaurin.

At the end of induction therapy, the rate of CR or CR with incomplete hematologic recovery (CRi) was 76.4 percent, which was similar between younger and older patients (75.8% for 18-60 years vs. 77.9% for 61-70 years; p=0.76). However, the mortality rate was higher among older than younger patients (10.5% vs. 3.5%; p=0.03).

The 247 participants (72.9%) who achieved a CR/CRi during induction proceeded to consolidation therapy with either alloHCT (n=207) or high-dose cytarabine with midostaurin (n=40).

Maintenance therapy (consisting of twice-daily midostaurin 50 mg for 365 days) was administered to 97 patients (34%): 75 of the 134 (56%) who underwent alloHCT and 22 of 40 (55%) who received high-dose cytarabine consolidation.

The median time on maintenance therapy after alloHCT and high-dose cytarabine was 9 months (range = 1-13) and 10.5 months (range = 1-12), respectively, and maintenance was terminated early in 44 patients (58.7%) and 16 patients (72.7%).

“Early discontinuation due to non-relapse causes was common after alloHCT (86%), whereas relapse and non-relapse causes were nearly equally distributed after [high-dose cytarabine],” the authors reported. “Thus, midostaurin maintenance therapy added some degree of toxicity, especially after alloHCT with anticipated interactions between midostaurin and immunosuppressants and anti-infectives.”

“The toxicity rates in our study were comparable to those observed in the RATIFY study [which supported midostaurin’s regulatory approval],” the authors reported. However, 22 percent of older patients experienced cardiac toxicities, which was “significantly more frequent as compared with previously reported cardiac event rates [which ranged from 3 to 7 percent] … highlighting the necessity of close ECG and electrolyte monitoring in this patient population.”

Older patients also experienced a higher frequency of pulmonary adverse events than younger patients (14% vs. 7%; p=0.07).

After a median follow-up of 28.9 months (range = 25-33.6):

  • median EFS: 13.2 months (range = 10.0-18.3)
  • median overall survival (OS): 26.0 months (range = 18.9-37.0)

Two-year EFS and OS rates were 37.7 percent and 50.9 percent, respectively.

“There was no difference in EFS according to age group (p=0.51), but a trend toward better OS in younger patients was observed in the multivariable analysis (p=0.07),” the authors reported.

According to an analysis comparing the present study with historical controls of five previous AML trials, midostaurin treatment improved EFS in both age subgroups (hazard ratio [HR] = 0.58; 95% CI 0.48-0.70; p<0.001). The risk reduction appeared to be greater for older patients (HR=0.61; 95% CI 0.49-0.67; p<0.001) than for younger patients (HR=0.42; 95% CI 0.29-0.61; p<0.001).

“Maintenance with midostaurin can be administered to only a fraction of patients after completion of intensive chemotherapy consolidation or alloHCT,” the researchers concluded. “Therefore, its role needs to be further explored preferably in a randomized setting with better-tolerated schedules and doses of midostaurin as well as better tolerable second-generation FLT3 inhibitors.”

Limitations of the study include its observational nature, potential confounders that were unmeasured and unadjusted in the multivariable analysis, and its lack of a randomized design and placebo or active comparator group.

The authors report relationships with Novartis, the manufacturer of midostaurin, which supported the trial.


Schlenk RF, Weber D, Fiedler W, et al. Midostaurin added to chemotherapy and continued single agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood. 2018 December 18. [Epub ahead of print]