Trial Outcomes & Findings for Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia (NCT NCT00651261)

Last Updated: 2021-08-18

Results Overview

Overall survival (OS) was defined as the time interval from randomization to death from any cause. The median OS with 95% CI was estimated using the Kaplan-Meier method.

Recruitment status

UNKNOWN

Study phase

PHASE3

Target enrollment

717 participants

Primary outcome timeframe

Duration of study (Up to 10 years)

Results posted on

2021-08-18

Participant Flow

Between May 2008 and October 2001, 3,277 participants were pre-registered. Of those, 900 participants had a documented FLT3 mutation. 717 participants were enrolled onto this study.

Participant milestones

Participant milestones
Measure	Induction and Consolidation Chemotherapy Plus Midostaurin Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.	Induction and Consolidation Chemotherapy Plus Placebo Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.
Overall Study STARTED	360	357
Overall Study COMPLETED	69	51
Overall Study NOT COMPLETED	291	306

Reasons for withdrawal

Reasons for withdrawal
Measure	Induction and Consolidation Chemotherapy Plus Midostaurin Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.	Induction and Consolidation Chemotherapy Plus Placebo Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.
Overall Study Adverse Event	32	22
Overall Study Death	18	18
Overall Study Withdrawal by Subject	22	40
Overall Study Induction failure	24	35
Overall Study Disease progression	58	58
Overall Study Alternative therapy	109	107
Overall Study Other disease or participant decisions	23	23
Overall Study Never treated	5	3

Baseline Characteristics

Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Induction and Consolidation Chemotherapy Plus Midostaurin n=360 Participants Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.	Induction and Consolidation Chemotherapy Plus Placebo n=357 Participants Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.	Total n=717 Participants Total of all reporting groups
Age, Continuous	47.1 years n=5 Participants	48.6 years n=7 Participants	47.9 years n=5 Participants
Sex: Female, Male Female	186 Participants n=5 Participants	212 Participants n=7 Participants	398 Participants n=5 Participants
Sex: Female, Male Male	174 Participants n=5 Participants	145 Participants n=7 Participants	319 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	9 Participants n=5 Participants	7 Participants n=7 Participants	16 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	103 Participants n=5 Participants	107 Participants n=7 Participants	210 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	248 Participants n=5 Participants	243 Participants n=7 Participants	491 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	8 Participants n=5 Participants	5 Participants n=7 Participants	13 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	8 Participants n=5 Participants	9 Participants n=7 Participants	17 Participants n=5 Participants
Race (NIH/OMB) White	147 Participants n=5 Participants	128 Participants n=7 Participants	275 Participants n=5 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	195 Participants n=5 Participants	213 Participants n=7 Participants	408 Participants n=5 Participants
Region of Enrollment Canada	4 participants n=5 Participants	9 participants n=7 Participants	13 participants n=5 Participants
Region of Enrollment United States	117 participants n=5 Participants	106 participants n=7 Participants	223 participants n=5 Participants
Region of Enrollment Germany	148 participants n=5 Participants	157 participants n=7 Participants	305 participants n=5 Participants
Region of Enrollment Belgium	3 participants n=5 Participants	5 participants n=7 Participants	8 participants n=5 Participants
Region of Enrollment France	3 participants n=5 Participants	2 participants n=7 Participants	5 participants n=5 Participants
Region of Enrollment Netherlands	3 participants n=5 Participants	2 participants n=7 Participants	5 participants n=5 Participants
Region of Enrollment Australia	0 participants n=5 Participants	2 participants n=7 Participants	2 participants n=5 Participants
Region of Enrollment Spain	7 participants n=5 Participants	15 participants n=7 Participants	22 participants n=5 Participants
Region of Enrollment Austria	7 participants n=5 Participants	5 participants n=7 Participants	12 participants n=5 Participants
Region of Enrollment Italy	61 participants n=5 Participants	44 participants n=7 Participants	105 participants n=5 Participants
Region of Enrollment Czech Republic	5 participants n=5 Participants	6 participants n=7 Participants	11 participants n=5 Participants
Region of Enrollment Slovakia	2 participants n=5 Participants	2 participants n=7 Participants	4 participants n=5 Participants
Region of Enrollment Hungary	0 participants n=5 Participants	2 participants n=7 Participants	2 participants n=5 Participants
FLT3 mutational subtype TKD (No ITD)	81 participants n=5 Participants	81 participants n=7 Participants	162 participants n=5 Participants
FLT3 mutational subtype ITD Allelic ratio <0.7	171 participants n=5 Participants	170 participants n=7 Participants	341 participants n=5 Participants
FLT3 mutational subtype ITD Allelic ratio >=0.7	108 participants n=5 Participants	106 participants n=7 Participants	214 participants n=5 Participants

PRIMARY outcome

Timeframe: Duration of study (Up to 10 years)

Overall survival (OS) was defined as the time interval from randomization to death from any cause. The median OS with 95% CI was estimated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Induction and Consolidation Chemotherapy Plus Midostaurin n=360 Participants Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.	Induction and Consolidation Chemotherapy Plus Placebo n=357 Participants Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.
Overall Survival (OS)	74.7 months Interval 31.5 to The upper limit was not calculable because an insufficient number of participants reached the event at the final time point for assessment.	25.6 months Interval 18.6 to 42.9

SECONDARY outcome

Timeframe: Duration of study (Up to 10 years)

Event free survival (EFS) was defined as the time from randomization until the earliest qualifying event, including: failure to obtain a CR on or before 60 days of initiation of protocol therapy; relapse; or death from any cause. Patients alive and event free at the time of analysis were censored on the date of last clinical assessment. The median EFS with 95% CI was estimated using the Kaplan-Meier method. Due to a higher than expected transplant rate, EFS was promoted to be a key secondary endpoint.

Outcome measures

Outcome measures
Measure	Induction and Consolidation Chemotherapy Plus Midostaurin n=360 Participants Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.	Induction and Consolidation Chemotherapy Plus Placebo n=357 Participants Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.
Event- Free Survival	8.2 months Interval 5.4 to 10.7	3.0 months Interval 1.9 to 5.9

SECONDARY outcome

Timeframe: Duration of study (Up to 10 years)

Overall survival (OS) was defined as the time interval from randomization to death from any cause. Any participants who received a stem cell transplant were censored at the time of transplant. The median OS with 95% CI was estimated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Induction and Consolidation Chemotherapy Plus Midostaurin n=360 Participants Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.	Induction and Consolidation Chemotherapy Plus Placebo n=357 Participants Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.
Overall Survival, Censoring Participants Who Receive a Stem Cell Transplant at the Time of the Transplant	NA months The median overall survival with censoring for transplant has not been reached	NA months Interval 27.4 to The median overall survival with censoring for transplant has not been reached

SECONDARY outcome

Timeframe: Induction therapy (up to 60 days)

Percentage of participants who achieved a complete response (CR). A CR was defined as normalization of blood counts and a marrow showing less than 5% blasts occurring on or before day 60.

Outcome measures

Outcome measures
Measure	Induction and Consolidation Chemotherapy Plus Midostaurin n=360 Participants Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.	Induction and Consolidation Chemotherapy Plus Placebo n=357 Participants Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.
Complete Response Rate	59 percentage of participants Interval 54.0 to 64.0	54 percentage of participants Interval 48.0 to 59.0

SECONDARY outcome

Timeframe: Duration of study (Up to 10 years)

Disease free survival (DFS) is defined as the time from documentation of first CR at any time to the first of relapse or death from any cause in participants who achieved a CR.

Outcome measures

Outcome measures
Measure	Induction and Consolidation Chemotherapy Plus Midostaurin n=360 Participants Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.	Induction and Consolidation Chemotherapy Plus Placebo n=357 Participants Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.
Disease-free Survival (DFS)	26.7 months Interval 19.4 to The upper limit was not calculable because an insufficient number of participants reached the event at the final time point for assessment.	15.5 months Interval 11.3 to 23.5

SECONDARY outcome

Timeframe: 30 months

Outcome measures

Outcome data not reported

Adverse Events

Induction and Consolidation Chemotherapy Plus Midostaurin

Serious events: 157 serious events

Other events: 321 other events

Deaths: 0 deaths

Induction and Consolidation Chemotherapy Plus Placebo

Serious events: 154 serious events

Other events: 324 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Richard Stone, MD

Dana Farber Cancer Institute

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Serious adverse events
Measure	Induction and Consolidation Chemotherapy Plus Midostaurin n=355 participants at risk Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.	Induction and Consolidation Chemotherapy Plus Placebo n=354 participants at risk Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.
Blood and lymphatic system disorders Blood disorder	0.00% 0/355 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Blood and lymphatic system disorders Bone marrow hypocellular	0.00% 0/355 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Blood and lymphatic system disorders Disseminated intravascular coagulation	0.28% 1/355 • Number of events 1 709 participants were evaluated for adverse events.	0.00% 0/354 709 participants were evaluated for adverse events.
Blood and lymphatic system disorders Febrile neutropenia	29.6% 105/355 • Number of events 144 709 participants were evaluated for adverse events.	31.1% 110/354 • Number of events 152 709 participants were evaluated for adverse events.
Blood and lymphatic system disorders Hemoglobin decreased	43.4% 154/355 • Number of events 237 709 participants were evaluated for adverse events.	41.8% 148/354 • Number of events 230 709 participants were evaluated for adverse events.
Blood and lymphatic system disorders Hemolysis	0.56% 2/355 • Number of events 2 709 participants were evaluated for adverse events.	0.00% 0/354 709 participants were evaluated for adverse events.
Blood and lymphatic system disorders Lymph node pain	0.00% 0/355 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Blood and lymphatic system disorders Lymphatic disorder	1.7% 6/355 • Number of events 6 709 participants were evaluated for adverse events.	1.1% 4/354 • Number of events 4 709 participants were evaluated for adverse events.
Cardiac disorders Arrhythmia	0.28% 1/355 • Number of events 1 709 participants were evaluated for adverse events.	0.56% 2/354 • Number of events 2 709 participants were evaluated for adverse events.
Cardiac disorders Asystole	0.28% 1/355 • Number of events 1 709 participants were evaluated for adverse events.	0.00% 0/354 709 participants were evaluated for adverse events.
Cardiac disorders Atrial fibrillation	1.1% 4/355 • Number of events 4 709 participants were evaluated for adverse events.	1.7% 6/354 • Number of events 6 709 participants were evaluated for adverse events.
Cardiac disorders Atrial flutter	0.56% 2/355 • Number of events 2 709 participants were evaluated for adverse events.	0.56% 2/354 • Number of events 2 709 participants were evaluated for adverse events.
Cardiac disorders Atrial tachycardia	0.28% 1/355 • Number of events 1 709 participants were evaluated for adverse events.	0.56% 2/354 • Number of events 2 709 participants were evaluated for adverse events.
Cardiac disorders Cardiac disorder	1.1% 4/355 • Number of events 4 709 participants were evaluated for adverse events.	1.7% 6/354 • Number of events 6 709 participants were evaluated for adverse events.
Cardiac disorders Cardiac pain	0.85% 3/355 • Number of events 3 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Cardiac disorders Cardiopulmonary arrest	0.00% 0/355 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Cardiac disorders Conduction disorder	0.00% 0/355 709 participants were evaluated for adverse events.	0.56% 2/354 • Number of events 2 709 participants were evaluated for adverse events.
Cardiac disorders Left ventricular dysfunction	0.28% 1/355 • Number of events 1 709 participants were evaluated for adverse events.	0.00% 0/354 709 participants were evaluated for adverse events.
Cardiac disorders Left ventricular failure	2.3% 8/355 • Number of events 9 709 participants were evaluated for adverse events.	2.0% 7/354 • Number of events 7 709 participants were evaluated for adverse events.
Cardiac disorders Myocardial ischemia	0.85% 3/355 • Number of events 3 709 participants were evaluated for adverse events.	0.85% 3/354 • Number of events 3 709 participants were evaluated for adverse events.
Cardiac disorders Palpitations	0.00% 0/355 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Cardiac disorders Pericardial effusion	1.1% 4/355 • Number of events 4 709 participants were evaluated for adverse events.	1.4% 5/354 • Number of events 5 709 participants were evaluated for adverse events.
Cardiac disorders Pericarditis	0.85% 3/355 • Number of events 3 709 participants were evaluated for adverse events.	0.00% 0/354 709 participants were evaluated for adverse events.
Cardiac disorders Right ventricular dysfunction	0.28% 1/355 • Number of events 1 709 participants were evaluated for adverse events.	0.00% 0/354 709 participants were evaluated for adverse events.
Cardiac disorders Sinus arrhythmia	0.28% 1/355 • Number of events 1 709 participants were evaluated for adverse events.	0.00% 0/354 709 participants were evaluated for adverse events.
Cardiac disorders Sinus bradycardia	0.56% 2/355 • Number of events 2 709 participants were evaluated for adverse events.	0.56% 2/354 • Number of events 2 709 participants were evaluated for adverse events.
Cardiac disorders Sinus tachycardia	4.8% 17/355 • Number of events 20 709 participants were evaluated for adverse events.	4.2% 15/354 • Number of events 20 709 participants were evaluated for adverse events.
Cardiac disorders Supraventricular tachycardia	0.00% 0/355 709 participants were evaluated for adverse events.	0.56% 2/354 • Number of events 2 709 participants were evaluated for adverse events.
Cardiac disorders Ventricular fibrillation	0.00% 0/355 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Cardiac disorders Ventricular tachycardia	0.00% 0/355 709 participants were evaluated for adverse events.	0.85% 3/354 • Number of events 3 709 participants were evaluated for adverse events.
Ear and labyrinth disorders Ear disorder	0.28% 1/355 • Number of events 1 709 participants were evaluated for adverse events.	0.56% 2/354 • Number of events 2 709 participants were evaluated for adverse events.
Ear and labyrinth disorders Ear pain	0.56% 2/355 • Number of events 2 709 participants were evaluated for adverse events.	0.85% 3/354 • Number of events 3 709 participants were evaluated for adverse events.
Ear and labyrinth disorders External ear pain	0.00% 0/355 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Ear and labyrinth disorders Middle ear inflammation	0.00% 0/355 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Ear and labyrinth disorders Tinnitus	0.00% 0/355 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Endocrine disorders Endocrine disorder	0.00% 0/355 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Endocrine disorders Hyperthyroidism	0.00% 0/355 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Endocrine disorders Hypothyroidism	0.00% 0/355 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Eye disorders Cataract	0.28% 1/355 • Number of events 1 709 participants were evaluated for adverse events.	0.00% 0/354 709 participants were evaluated for adverse events.
Eye disorders Conjunctivitis	0.56% 2/355 • Number of events 2 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.

Other adverse events
Measure	Induction and Consolidation Chemotherapy Plus Midostaurin n=355 participants at risk Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.	Induction and Consolidation Chemotherapy Plus Placebo n=354 participants at risk Patients will receive daunorubicin 60 mg/m\^2 by IV push days 1-3 plus cytarabine 200 mg/m\^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m\^2) days 1, 3, \& 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.
Blood and lymphatic system disorders Blood disorder	1.4% 5/355 • Number of events 11 709 participants were evaluated for adverse events.	1.1% 4/354 • Number of events 6 709 participants were evaluated for adverse events.
Blood and lymphatic system disorders Disseminated intravascular coagulation	0.56% 2/355 • Number of events 2 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Blood and lymphatic system disorders Febrile neutropenia	69.3% 246/355 • Number of events 422 709 participants were evaluated for adverse events.	67.2% 238/354 • Number of events 394 709 participants were evaluated for adverse events.
Blood and lymphatic system disorders Hemoglobin decreased	87.9% 312/355 • Number of events 1059 709 participants were evaluated for adverse events.	87.9% 311/354 • Number of events 940 709 participants were evaluated for adverse events.
Blood and lymphatic system disorders Lymph node pain	0.56% 2/355 • Number of events 2 709 participants were evaluated for adverse events.	0.00% 0/354 709 participants were evaluated for adverse events.
Blood and lymphatic system disorders Lymphatic disorder	2.8% 10/355 • Number of events 13 709 participants were evaluated for adverse events.	2.5% 9/354 • Number of events 11 709 participants were evaluated for adverse events.
Cardiac disorders Arrhythmia	0.28% 1/355 • Number of events 1 709 participants were evaluated for adverse events.	1.1% 4/354 • Number of events 4 709 participants were evaluated for adverse events.
Cardiac disorders Atrial fibrillation	0.85% 3/355 • Number of events 3 709 participants were evaluated for adverse events.	0.00% 0/354 709 participants were evaluated for adverse events.
Cardiac disorders Atrial flutter	0.00% 0/355 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Cardiac disorders Atrial tachycardia	0.28% 1/355 • Number of events 3 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Cardiac disorders Cardiac disorder	2.3% 8/355 • Number of events 12 709 participants were evaluated for adverse events.	3.7% 13/354 • Number of events 17 709 participants were evaluated for adverse events.
Cardiac disorders Cardiac pain	1.1% 4/355 • Number of events 6 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Cardiac disorders Cardiac valve disease	0.00% 0/355 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Cardiac disorders Conduction disorder	0.28% 1/355 • Number of events 1 709 participants were evaluated for adverse events.	0.56% 2/354 • Number of events 2 709 participants were evaluated for adverse events.
Cardiac disorders Left ventricular failure	1.7% 6/355 • Number of events 6 709 participants were evaluated for adverse events.	1.4% 5/354 • Number of events 9 709 participants were evaluated for adverse events.
Cardiac disorders Myocardial ischemia	0.28% 1/355 • Number of events 1 709 participants were evaluated for adverse events.	0.00% 0/354 709 participants were evaluated for adverse events.
Cardiac disorders Palpitations	0.85% 3/355 • Number of events 3 709 participants were evaluated for adverse events.	1.4% 5/354 • Number of events 13 709 participants were evaluated for adverse events.
Cardiac disorders Pericardial effusion	2.0% 7/355 • Number of events 8 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Cardiac disorders Pericarditis	0.56% 2/355 • Number of events 2 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Cardiac disorders Premature ventricular contractions	0.28% 1/355 • Number of events 3 709 participants were evaluated for adverse events.	0.00% 0/354 709 participants were evaluated for adverse events.
Cardiac disorders Sinus bradycardia	2.8% 10/355 • Number of events 10 709 participants were evaluated for adverse events.	1.4% 5/354 • Number of events 15 709 participants were evaluated for adverse events.
Cardiac disorders Sinus tachycardia	3.1% 11/355 • Number of events 13 709 participants were evaluated for adverse events.	6.5% 23/354 • Number of events 29 709 participants were evaluated for adverse events.
Cardiac disorders Supraventricular extrasystoles	0.28% 1/355 • Number of events 1 709 participants were evaluated for adverse events.	0.56% 2/354 • Number of events 7 709 participants were evaluated for adverse events.
Cardiac disorders Supraventricular tachycardia	0.28% 1/355 • Number of events 1 709 participants were evaluated for adverse events.	0.56% 2/354 • Number of events 2 709 participants were evaluated for adverse events.
Cardiac disorders Ventricular arrhythmia	0.28% 1/355 • Number of events 1 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Cardiac disorders Ventricular bigeminy	0.28% 1/355 • Number of events 2 709 participants were evaluated for adverse events.	0.00% 0/354 709 participants were evaluated for adverse events.
Cardiac disorders Ventricular fibrillation	0.28% 1/355 • Number of events 1 709 participants were evaluated for adverse events.	0.00% 0/354 709 participants were evaluated for adverse events.
Cardiac disorders Ventricular tachycardia	0.28% 1/355 • Number of events 1 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Ear and labyrinth disorders Ear disorder	1.4% 5/355 • Number of events 5 709 participants were evaluated for adverse events.	0.85% 3/354 • Number of events 3 709 participants were evaluated for adverse events.
Ear and labyrinth disorders Ear pain	1.4% 5/355 • Number of events 6 709 participants were evaluated for adverse events.	1.7% 6/354 • Number of events 6 709 participants were evaluated for adverse events.
Ear and labyrinth disorders External ear inflammation	0.00% 0/355 709 participants were evaluated for adverse events.	0.56% 2/354 • Number of events 2 709 participants were evaluated for adverse events.
Ear and labyrinth disorders External ear pain	0.85% 3/355 • Number of events 3 709 participants were evaluated for adverse events.	0.56% 2/354 • Number of events 2 709 participants were evaluated for adverse events.
Ear and labyrinth disorders Hearing impaired	0.56% 2/355 • Number of events 4 709 participants were evaluated for adverse events.	0.56% 2/354 • Number of events 2 709 participants were evaluated for adverse events.
Ear and labyrinth disorders Middle ear inflammation	0.00% 0/355 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 1 709 participants were evaluated for adverse events.
Ear and labyrinth disorders Tinnitus	0.85% 3/355 • Number of events 3 709 participants were evaluated for adverse events.	0.56% 2/354 • Number of events 2 709 participants were evaluated for adverse events.
Endocrine disorders Endocrine disorder	0.28% 1/355 • Number of events 1 709 participants were evaluated for adverse events.	0.56% 2/354 • Number of events 2 709 participants were evaluated for adverse events.
Endocrine disorders Hyperthyroidism	0.56% 2/355 • Number of events 7 709 participants were evaluated for adverse events.	0.28% 1/354 • Number of events 3 709 participants were evaluated for adverse events.
Endocrine disorders Hypothyroidism	0.56% 2/355 • Number of events 2 709 participants were evaluated for adverse events.	0.56% 2/354 • Number of events 5 709 participants were evaluated for adverse events.
Eye disorders Cataract	0.28% 1/355 • Number of events 9 709 participants were evaluated for adverse events.	0.00% 0/354 709 participants were evaluated for adverse events.
Eye disorders Conjunctivitis	2.0% 7/355 • Number of events 7 709 participants were evaluated for adverse events.	1.1% 4/354 • Number of events 5 709 participants were evaluated for adverse events.