Efficacy and safety of midostaurin in younger and older patients with FLT3-ITD AML

Midostaurin is a FLT3-ITD inhibitor approved by the U.S. Food and Drug Administration (FDA) and European Commission (EC) for newly diagnosed AML in adult patients with FLT3-mutated AML. This decision followed results from the RATIFY trial which demonstrated midostaurin and intensive chemotherapy improved event-free survival (EFS) and overall survival (OS) compared with placebo. In the recent phase II AMLSG 16-10 trial (NCT01477606), older patients aged 61–70 years old were included in the treatment cohort with midostaurin. Interim study results have been previously reported by the AML Hub. Here, we summarize the key efficacy and safety results, published by Döhner et al.¹, in Blood Advances.

Methods

The AMLSG 16-10 was a single arm, phase II study¹ conducted at 54 centres in Austria and Germany. The outcomes of patients enrolled in this trial were compared with those of a historical control cohort (AMLSG). Patient inclusion criteria and study endpoints are shown in Figure 1.

Allo-HSCT, allogeneic hematopoietic stem cell transplant; AML, acute myeloid leukemia; CBF-AML, core-binding factor AML; CID, cumulative incidence of death; CIR, cumulative incidence of relapse; CR/CRi, complete remission/complete remission with incomplete hematologic recovery; CTCAE, Common Terminology Criteria for Adverse Events; RFS, relapse-free survival.
*Adapted from Döhner et al.¹

Results

Patient characteristics for the AMLSG 16-10 and AMLSG historical cohort are shown in Table 1.

Table 1. Patient characteristics*

BM, bone marrow; Hb, hemoglobin; ECOG, Eastern Cooperative Oncology Group; PB, peripheral blood; WBC, white blood cell. *Table from Döhner et al.1
Characteristic	AMLSG 16-10 cohort (n = 440)	AMLSG historical cohort (n = 415)	p value
Median age, years (range)	54.1 (18–70)	50.5 (18–70)	< 0.001
Female, %	57	54
ECOG PS, %			< 0.0001
0	38	22
1	50	61
2	12	16
WBC, × 109/L
Median (range)	41.8 (0.3–420)	44.8 (0.2–439)
Missing, n	3	3
Hb, g/dL
Median (range)	9.0 (4.1–18.1)	9.0 (3.1–16.6)
Missing, n	4	3
Platelet count, × 109/L
Median (range)	59 (5–681)	58 (6–734)
Missing, n	3	2
BM blasts, %
Median (range)	80 (0–100)	85 (2–100)
Missing, n	46	25
PB blasts, %
Median (range)	52 (0–100)	60 (0–100)
Missing, n	30	20
AML type, %			< 0.0001
De novo	89	91
Secondary	7	1
Therapy-related	4	3
Missing, n	—	1
Cytogenetics, %			0.02
Intermediate-I	69	78
Intermediate-II	25	17
Adverse	6	5
Missing, n	28	0
FLT3-ITD, %
Allelic ratio ≥0.5	55	56
Missing, n	2	121
FLT3-TKD present, %	4	4
Missing, n	—	22

Efficacy

• The median follow-up for the AMLSG 16-10 and historical cohort was 40.4 months and 76.3 months, respectively
• The 2-year EFS and OS were greater in the AMLSG 16-10 cohort treated with midostaurin compared to the historical cohort (Figure 2)
  • The AMLSG 16-10 cohort also showed improved EFS and OS when assessing via subgroup analysis for younger (18–60 years) and older (61–70) patients

*Adapted from Döhner et al.¹

• In a multivariate analysis, midostaurin treatment in the AMLSG 16-10 trial was associated with significantly improved OS and EFS compared with the historical cohort (Table 2)
  • This effect was again observed in both younger and older patients.

Table 2. Multivariate analysis*

CI, confidence interval; EFS, event-free survival; HR, hazard ratio; OS, overall survival; WBC, white blood cell. *Adapted from Döhner et al.1
Variable	EFS		OS
	HR (95% CI)	p value	HR (95% CI)	p value
All patients (N = 855)
AMLSG 16-10	0.55 (0.47–0.65)	<0.001	0.56 (0.47–0.68)	<0.001
Age (per 10 years)	1.17 (1.09–1.25)	<0.001	1.33 (1.23–1.44)	<0.001
NPM1-mutated	0.48 (0.41–0.57)	<0.001	0.76 (0.63–0.91)	0.002
WBC	1.21 (1.05–1.40)	0.011	1.23 (1.04–1.44)	0.015
18–60 years (n = 664)
AMLSG 16-10	0.59 (0.49–0.71)	<0.001	0.59 (0.47–0.73)	<0.001
Age (per 10 years)	1.16 (1.06–1.27)	<0.001	1.30 (1.17–1.45)	<0.001
NPM1-mutated	0.47 (0.39–0.56)	<0.001	0.76 (0.61–0.94)	0.010
WBC	1.24 (1.04–1.47)	0.014	1.23 (1.01–1.49)	0.037
61–70 years (n = 191)
AMLSG 16-10	0.41 (0.29–0.59)	<0.001	0.47 (0.33–0.67)	<0.001
Female sex	—	—	0.70 (0.49–0.99)	0.042
NPM1-mutated	0.53 (0.38–0.74)	<0.001	—	—

• In a sensitivity analysis, allogeneic hematopoietic stem cell transplantation (allo-HSCT) slightly reduced the treatment effect compared to the multivariate model without considering allo-HSCT (EFS: HR 0.63 and 0.62 vs 0.55; OS: HR 0.72 and 0.66 vs 0.57)
• When comparing patients from AMLSG 16-10 with the RATIFY trial, the treatment effect of midostaurin remained significant (HR, 0.71; p = 0.005)
• Treatment with midostaurin produced significantly greater complete remission/complete remission with incomplete hematologic recovery (CR/CRi) compared with the historical cohort, and lower cumulative incidence of relapse (CIR) and rates of refractory disease
  • The 2-year RFS rate in the AMLSG 16-10 trial was 52% and in the historical population was 32%, and multivariate analysis revealed treatment within the AMLSG 16-10 trial (HR, 0.50; p < 0.001) and NPM1 mutation (HR, 0.63; P < 0.001) as significant favorable factors, while older age (HR per 10 years, 1.02; p < 0.001) was an adverse factor.

Table 3. Analysis of secondary endpoints*

CID, cumulative incidence of death; CIR, cumulative incidence of relapse; CR/CRi, complete remission/complete remission with incomplete hematologic recovery; ED, early death; HD, hypoplastic death; RD, refractory disease. *Table from Döhner et al.1
Outcomes, % (unless otherwise stated)	AMLSG 16-10 cohort			Historical cohort
	All patients (N = 440)	18–60 years (n = 312)	61–70 years (n = 128)	All patients (N = 415)	18–60 years (n = 352)	61–70 years (n = 63)
CR/CRi	74.9	75.9	72.4	64.6	66.5	54.0
CIR	28.0	24.0	37.0	57.0	54.0	74.0
CID	20.0	20.0	19.0	12.0	12.0	12.0
RD	19.2	20.6	15.8	30.6	28.4	42.9
ED/HD	5.9	3.5	11.8	4.8	5.1	3.2
Missing, n	2	1	1	—	—	—

Safety

• Midostaurin treatment was interrupted at least once in 40% of patients, mostly due to toxicity (73%)
  • The most frequent adverse events (AEs) leading to treatment discontinuation were thrombocytopenia, nausea/vomiting, graft-versus-host disease (GvHD), hepatobiliary disease/increase of transaminases, and infections
• Grade ≥3 AEs are summarized in Table 4.
  • Metabolism and nutrition disorders (p = 0.003), vascular disorders (p = 0.04), cardiac disorders (p = 0.08), and respiratory, thoracic, and mediastinal disorders (p = 0.07) were more common in older (61–70 years) patients

Table 4. Grade ≥3 AEs occurring in >10% of patients*

AEs, adverse events. *Table from Döhner et al.1
AEs, %	Patients (N = 440)
Blood and lymphatic system disorders	95
Infections and infestations	66
Gastrointestinal	39
General disorders	34
Investigations	30
Metabolism and nutrition disorders	27
Respiratory, thoracic, and mediastinal	17
Vascular	15
Renal and urinary	12
Nervous system	10
Cardiac	10
Skin and subcutaneous tissue	10

Conclusion

Results from the phase II study¹ showed the benefits of midostaurin in patients with FLT3-ITD-mutant AML. In line with the previous RATIFY trial, compared to historical controls, treatment with midostaurin significantly improved the survival outcomes in older and younger patients with FLT3-ITD-positive AML with a manageable safety profile.