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Clinical Trial Results:
Phase III study of chemotherapy in combination with ATRA with or without gemtuzumab ozogamicin in patients with acute myeloid leukemia and NPM1 gene mutation

Summary
EudraCT number	2009-011889-28
Trial protocol	DE AT
Global end of trial date	01 Sep 2021

Results information
Results version number	v1(current)
This version publication date	16 Sep 2022
First version publication date	16 Sep 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

AMLSG09-09

ISRCTN number

US NCT number

NCT00893399

WHO universal trial number (UTN)

Sponsor organisation name

University of Ulm

Sponsor organisation address

Albert-Einstein-Allee 23, Ulm, Germany, 89081

Public contact

AMLSG clinical trial office, University of Ulm, 049 731500 56072, daniela.weber@uniklinik-ulm.de

Scientific contact

AMLSG clinical trial office, University of Ulm, 3150045980 731500 56072, daniela.weber@uniklinik-ulm.de

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

01 Jul 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

01 Sep 2021

Global end of trial reached?

Yes

Global end of trial date

01 Sep 2021

Was the trial ended prematurely?

Main objective of the trial

Primary Efficacy Objective • Evaluation of efficacy based on short-term event-free survival (EFS) and overall survival (OS) after induction and consolidation chemotherapy plus all-trans retinoic acid (ATRA) with or without gemtuzumab ozogamicin (GO) in adult patients with acute myeloid leu-kemia (AML) and nucleophosmin-1 (NPM1) mutation Secondary Efficacy Objectives • Evaluation of efficacy based on complete remission (CR, CR/CRh, CR/CRi) rates, event-free survival (EFS), cumulative incidences of relapse (CIR) and death (CID) in CR/CRi Safety and QoL Objectives • Evaluation of safety based on toxicity induced by gemtuzumab ozogamicin (GO) • Evaluation of safety based on duration of neutropenia and leukopenia after consolidation therapy, incidence of infection, duration of hospitalization • Assessment of quality of life

Protection of trial subjects

In this study, safety was assessed by evaluating the following: reported adverse events, clinical laboratory test results, vital signs measurements, ECG findings, chest X-ray, echo scan, physical examination findings, monitoring of concomitant therapy. For each safety parameter, all findings (whether normal or abnormal) were recorded in the CRF.

Background therapy

Evidence for comparator

Actual start date of recruitment

12 May 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 59

Country: Number of subjects enrolled

Germany: 529

Worldwide total number of subjects

588

EEA total number of subjects

588

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

398

From 65 to 84 years

190

85 years and over

Subject disposition

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Recruitment details

First patient in: 12.05.2010 Last patient last visit: 01.09.2021 Recruitment was interrupted 3 times during the study: 1st interruption 01.06.2010 - 14.10.2010 due to withdrawal of marketing authorization of GO 2nd interruption 22.12.2011 - 23.04.2012 due to urgent amendment 3rd interruption 27.09.2013 - 20.12.2013 due increase of sample size

Screening details

Screening details: Molecular genetic analysis (central AMLSG reference lab) of blood and bone marrow was performed at baseline within 48 hours to make an enrollment possible.

Number of subjects started

588

Number of subjects completed

588

Period 1 title

Overall trial period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Arm A: ATRA

Arm description

Arm type

Active comparator

Investigational medicinal product name

Cytarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

In the first induction cycle, cytarabine was administered by continuous intravenous infusion in a dose of 100 mg/m2 from day 1 to day 7. In the second induction cycle, cytarabine was administered by intravenous infusion in a dose of 100 mg/m2 from day 1 to day 5. In all consolidation cycles, cytarabine was administered by intravenous infusion in a dose of 3 g/m2 twice a day on days 1, 2 and 3. For patients > 60 years of age, dose of cytarabine was reduced to 1 g/m2.

Investigational medicinal product name

Idarubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous bolus use

Dosage and administration details

In the first induction cycle, idarubicin was administered by intravenous push in a dose of 12 mg/m2 on days 1, 3 and 5 in patients ≤ 60 years of age and on day 1 and day 3 in patients > 60 years of age. In the second induction cycle, idarubicin was administered by intravenous push in a dose of 10 mg/m2 on days 1 and 3 for both patients ≤ 60 years of age and patients > 60 years of age.

Investigational medicinal product name

Etoposide

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

In the first induction cycle, etoposide was administered by intravenous infusion in a dose of 100 mg/m2 on days 1, 2 and 3. For patients > 60 years of age administration of etoposide was scheduled only on day 1 and day 3. In the second induction cycle, etoposide was scheduled on day 1 and day 3 in a dose of 100 mg/m2.

Investigational medicinal product name

All-trans retinoic acid (ATRA)

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

In the induction cycles, ATRA was administered orally in a daily dose of 45 mg/m2 from day 6 to day 8 and thereafter in a daily dose of 15 mg/m2 from day 9 to day 21. During consolidation cycles, ATRA was administered orally in a daily dose of 15 mg/m2 from day 4 up to day 21.

Investigational medicinal product name

Pegfilgrastim

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Pegfilgrastim was administered subcutaneously in a dose of 6 mg on day 10 in the consolidation cycles.

Arm B: GO+ATRA

Arm description

Arm type

Experimental

Investigational medicinal product name

Cytarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Idarubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous bolus use

Dosage and administration details

Investigational medicinal product name

Etoposide

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

All-trans retinoic acid (ATRA)

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Pegfilgrastim

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Pegfilgrastim was administered subcutaneously in a dose of 6 mg on day 10 in the consolidation cycles.

Investigational medicinal product name

Gemtuzumab ozogamicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Gemtuzumab ozogamicin was administered by intravenous infusion in a dose of 3 mg/m2 on day 1 of the treatment cycle, in the first and second induction cycle and the first consolidation cycle.

Number of subjects in period 1	Arm A: ATRA	Arm B: GO+ATRA
Started	296	292
Completed	194	170
Not completed	102	122
Adverse event, serious fatal	18	35
Consent withdrawn by subject	6	3
Allogeneic HCT	23	22
Death before start of treatment	1	2
Adverse event, non-fatal	25	42
Other reason	3	2
Lack of efficacy	26	16

Baseline characteristics

Top of page

Reporting group title

Arm A: ATRA

Reporting group description

Reporting group title

Arm B: GO+ATRA

Reporting group description

Reporting group values	Arm A: ATRA	Arm B: GO+ATRA	Total
Number of subjects	296	292	588
Age categorical
Units: Subjects
18 - 60 years	165	160	325
>60 years	131	132	263
Age continuous
Units: years
median (full range (min-max))	58.8 (20.9 to 80.2)	58.7 (18.4 to 82.3)	-
Gender categorical
Units: Subjects
Female	152	163	315
Male	144	129	273
Ethnicity
Units: Subjects
Caucasian	291	285	576
Asian	1	0	1
North African / Arabian / Turk	4	5	9
Other African	0	1	1
Other	0	1	1
History of AML
Units: Subjects
De novo AML	276	271	547
sAML	3	7	10
tAML	17	14	31
ELN risk 2010
Units: Subjects
Favorable	194	193	387
Intermediate-I	37	42	79
Intermediate-II	29	35	64
Adverse	3	3	6
Missing values	33	19	52
Normal karyotype
Units: Subjects
No	32	38	70
Yes	231	235	466
Missing values	33	19	52
FLT3-ITD mutation status
Units: Subjects
Negative	247	242	489
Positive	49	50	99
FLT3-TKD mutation status
Units: Subjects
Negative	262	250	512
Positive	34	42	76
DNMT3A
Units: Subjects
Negative	153	129	282
Positive	141	158	299
Missing values	2	5	7
White blood cell count
Units: Giga/l
median (full range (min-max))	20.5 (0.00204 to 296)	16.9 (0.0615 to 279)	-
Hemoglobin
Units: g/dl
median (full range (min-max))	9.35 (4.3 to 19.3)	9.10 (4.4 to 15.0)	-
Platelets
Units: Giga/l
median (full range (min-max))	69.5 (3 to 660)	74.0 (7 to 404)	-
Bone marrow blast count
Units: Percent (%)
median (full range (min-max))	71 (3 to 100)	76.5 (0 to 100)	-
Peripheral blood count
Units: Percent (%)
median (full range (min-max))	25 (0 to 99)	26 (0 to 99)	-
LDH
Units: U/l
median (full range (min-max))	439 (86 to 5650)	426 (137 to 9670)	-

Subject analysis set title

ITT population

Subject analysis set type

Intention-to-treat

Subject analysis set description

ITT population comprises all randomized eligible patients. Patients were analyzed according to the treatment group allocated at randomization.

Subject analysis set title

Safety population

Subject analysis set type

Safety analysis

Subject analysis set description

The safety analysis set includes all patients from the ITT population who have received at least one dose of any study medication. Treatment arms are aligned according to what treatment the patients actually have received.

Subject analysis sets values	ITT population	Safety population
Number of subjects	588	585
Age categorical
Units: Subjects
18 - 60 years	325
>60 years	263
Age continuous
Units: years
median (full range (min-max))	58.7 (18.4 to 82.3)
Gender categorical
Units: Subjects
Female	315
Male	273
Ethnicity
Units: Subjects
Caucasian	576
Asian	1
North African / Arabian / Turk	9
Other African	1
Other	1
History of AML
Units: Subjects
De novo AML	547
sAML	10
tAML	31
ELN risk 2010
Units: Subjects
Favorable	387
Intermediate-I	79
Intermediate-II	64
Adverse	6
Missing values	52
Normal karyotype
Units: Subjects
No	70
Yes	466
Missing values	52
FLT3-ITD mutation status
Units: Subjects
Negative	489
Positive	99
FLT3-TKD mutation status
Units: Subjects
Negative	512
Positive	76
DNMT3A
Units: Subjects
Negative	282
Positive	299
Missing values	7
White blood cell count
Units: Giga/l
median (full range (min-max))	19.1 (0.00204 to 296)
Hemoglobin
Units: g/dl
median (full range (min-max))	9.2 (4.3 to 19.3)
Platelets
Units: Giga/l
median (full range (min-max))	73.0 (3 to 660)
Bone marrow blast count
Units: Percent (%)
median (full range (min-max))	74 (0 to 100)
Peripheral blood count
Units: Percent (%)
median (full range (min-max))	26 (0 to 99)
LDH
Units: U/l
median (full range (min-max))	437 (86 to 9670)

End points

Top of page

Reporting group title

Arm A: ATRA

Reporting group description

Reporting group title

Arm B: GO+ATRA

Reporting group description

Subject analysis set title

ITT population

Subject analysis set type

Intention-to-treat

Subject analysis set description

ITT population comprises all randomized eligible patients. Patients were analyzed according to the treatment group allocated at randomization.

Subject analysis set title

Safety population

Subject analysis set type

Safety analysis

Subject analysis set description

Primary: Overall Survival

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End point title

Overall Survival

End point description

End point type

Primary

End point timeframe

after 48 months

End point values	Arm A: ATRA	Arm B: GO+ATRA	ITT population
Number of subjects analysed	296	292	588
Units: Rate
number (confidence interval 95%)	0.61 (0.55 to 0.66)	0.64 (0.58 to 0.69)	0.62 (0.58 to 0.66)

Attachments

Overall survival (all patients)
Overall survival (according to treatment arm)
Overall survival (according to treatment and age)

Primary analysis Overall Survival (univariate)

Statistical analysis description

Univariate analysis

Comparison groups

Arm A: ATRA v Arm B: GO+ATRA

Number of subjects included in analysis

588

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.427

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

1.16

Cox Regression on OS

Statistical analysis description

multivariate analysis

Comparison groups

Arm A: ATRA v Arm B: GO+ATRA

Number of subjects included in analysis

588

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.713

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.74

upper limit

1.23

Secondary: Event-free survival (original definition, ELN 2017)

Top of page

End point title

Event-free survival (original definition, ELN 2017)

End point description

Patients with no response after induction cycle 1 had an event at the date of response assessment after induction 1. Patients with refractory disease after induction cycle 2 had an event at the date of response assessment after induction 2. Patients with relapse after achieving CR/CRi by the end of induction treatment had an event at the date of relapse. Patients who died during induction of after achieving CR/CRi by the end of induction therapy had an event at the date of death. Non-events are censored at the date of last known alive.

End point type

Secondary

End point timeframe

after 48 months

End point values	Arm A: ATRA	Arm B: GO+ATRA	ITT population
Number of subjects analysed	296	292	588
Units: Rate
number (confidence interval 95%)	0.47 (0.41 to 0.52)	0.53 (0.47 to 0.59)	0.50 (0.45 to 0.54)

Attachments

EFS original definition (all patients)
EFS original definition (acc. to treatment arm)
EFS original definition (acc. treatment and age)

Univariate analysis on EFS (original definition)

Comparison groups

Arm A: ATRA v Arm B: GO+ATRA

Number of subjects included in analysis

588

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.093

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.66

upper limit

1.03

Cox Regression on EFS (original definition)

Statistical analysis description

multivariate analysis

Comparison groups

Arm A: ATRA v Arm B: GO+ATRA

Number of subjects included in analysis

588

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.092

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.82

Confidence interval

level

95%

sides

2-sided

lower limit

0.66

upper limit

1.03

Secondary: Event-free survival (ELN 2022)

Top of page

End point title

Event-free survival (ELN 2022)

End point description

Patients who failed to achieve CR/CRi by the end of induction treatment had an event on day 1 post randomization. Patient with morphologic relapse after achieving CR/CRi by end of induction treatment had an event at the date of relapse. Patients who died without a relapse after achieving CR/CRi by the end of induction treatment had an event at the date of death. Patients who started a new non-study treatment due to confirmed molecular progression or relapse without prior morphologic relapse after achieving a CR/CRi by the end of induction treatment had an event at the date of start of new treatment. Non-events were censored at the date of last response evaluation. If no response assessment after study inclusion: Day 1 post-randomization.

End point type

Secondary

End point timeframe

after 48 months

End point values	Arm A: ATRA	Arm B: GO+ATRA	ITT population
Number of subjects analysed	296	292	588
Units: Rate
number (confidence interval 95%)	0.41 (0.35 to 0.47)	0.48 (0.42 to 0.54)	0.45 (0.40 to 0.49)

Attachments

Event-free survival - ELN 2022 (all patients)
EFS ELN 2022 (according to treatment arm)
EFS ELN 2022 (acc. treatment and age)

Univariate analysis on EFS (ELN 2022 definition)

Comparison groups

Arm A: ATRA v Arm B: GO+ATRA

Number of subjects included in analysis

588

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.078

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.67

upper limit

1.03

Cox Regression on EFS (ELN 2022) multivariate

Statistical analysis description

multivariate analysis

Comparison groups

Arm B: GO+ATRA v Arm A: ATRA

Number of subjects included in analysis

588

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.069

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.81

Confidence interval

level

95%

sides

2-sided

lower limit

0.65

upper limit

1.02

Secondary: Rate of CR

Top of page

End point title

Rate of CR

End point description

End point type

Secondary

End point timeframe

within two months (after induction therapy)

End point values	Arm A: ATRA	Arm B: GO+ATRA	ITT population
Number of subjects analysed	296	292	588
Units: Rate
number (not applicable)	58.1	46.6	52.4

Mantel-Haenszel Test Rate of CR

Comparison groups

Arm A: ATRA v Arm B: GO+ATRA

Number of subjects included in analysis

588

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.007

Method

Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.63

Confidence interval

level

95%

sides

2-sided

lower limit

0.45

upper limit

0.87

Logistic regression on CR rate

Statistical analysis description

multivariate analysis

Comparison groups

Arm A: ATRA v Arm B: GO+ATRA

Number of subjects included in analysis

588

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.006

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.63

Confidence interval

level

95%

sides

2-sided

lower limit

0.45

upper limit

0.87

Secondary: Rate of CR/CRi

Top of page

End point title

Rate of CR/CRi

End point description

End point type

Secondary

End point timeframe

within 2 months (after induction therapy)

End point values	Arm A: ATRA	Arm B: GO+ATRA	ITT population
Number of subjects analysed	296	292	588
Units: Rate
number (not applicable)	90.2	86.0	88.1

Mantel-Haenszel Test Rate of CR/CRi

Comparison groups

Arm A: ATRA v Arm B: GO+ATRA

Number of subjects included in analysis

588

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.149

Method

Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.4

upper limit

1.11

Logistic regression on CR/CRi rate

Comparison groups

Arm A: ATRA v Arm B: GO+ATRA

Number of subjects included in analysis

588

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.083

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.63

Confidence interval

level

95%

sides

2-sided

lower limit

0.37

upper limit

1.06

Secondary: Rate of CR/CRh

Top of page

End point title

Rate of CR/CRh

End point description

End point type

Secondary

End point timeframe

within 2 months (after induction therapy)

End point values	Arm A: ATRA	Arm B: GO+ATRA	ITT population
Number of subjects analysed	296	292	588
Units: Rate
number (not applicable)	72.3	66.8	69.6

Mantel-Haenszel Test Rate of CR/CRh

Comparison groups

Arm A: ATRA v Arm B: GO+ATRA

Number of subjects included in analysis

588

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.178

Method

Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

1.1

Logistic regression on CR/CRh rate

Comparison groups

Arm A: ATRA v Arm B: GO+ATRA

Number of subjects included in analysis

588

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.123

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.76

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

1.08

Secondary: Cumulative incidence of relapse

Top of page

End point title

Cumulative incidence of relapse

End point description

End point type

Secondary

End point timeframe

after 48 months

End point values	Arm A: ATRA	Arm B: GO+ATRA	ITT population
Number of subjects analysed	267	251	518
Units: Rate
number (confidence interval 95%)	0.42 (0.36 to 0.48)	0.30 (0.25 to 0.36)	0.36 (0.32 to 0.40)

Attachments

CIR (all patients)
CIR (according to treatment arm)
CIR (acc. treatment and age)

Cause-specific Cox regression on CIR

Comparison groups

Arm A: ATRA v Arm B: GO+ATRA

Number of subjects included in analysis

518

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.65

Confidence interval

level

95%

sides

2-sided

lower limit

0.49

upper limit

0.86

Cox regression on CIR multivariate

Comparison groups

Arm A: ATRA v Arm B: GO+ATRA

Number of subjects included in analysis

518

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.45

upper limit

0.81

Secondary: Cumulative incidence of death

Top of page

End point title

Cumulative incidence of death

End point description

End point type

Secondary

End point timeframe

after 48 months

End point values	Arm A: ATRA	Arm B: GO+ATRA	ITT population
Number of subjects analysed	267	251	518
Units: Rate
number (confidence interval 95%)	0.07 (0.05 to 0.11)	0.08 (0.05 to 0.12)	0.08 (0.06 to 0.11)

Attachments

CID (all patients)
CID (according to treatment arm)
CID (acc. to treatment and age)

Cause-specific Cox regression on CID

Comparison groups

Arm A: ATRA v Arm B: GO+ATRA

Number of subjects included in analysis

518

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.907

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.59

upper limit

1.81

Cox regression on CID multivariate

Comparison groups

Arm A: ATRA v Arm B: GO+ATRA

Number of subjects included in analysis

518

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.816

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

1.9

Secondary: 30-day mortality

Top of page

End point title

30-day mortality

End point description

End point type

Secondary

End point timeframe

30 days

End point values	Arm A: ATRA	Arm B: GO+ATRA	Safety population
Number of subjects analysed	295	290	585
Units: Rate
number (confidence interval 95%)	0.04 (0.02 to 0.06)	0.07 (0.04 to 0.10)	0.05 (0.03 to 0.07)

No statistical analyses for this end point

Secondary: 60-day mortality

Top of page

End point title

60-day mortality

End point description

End point type

Secondary

End point timeframe

60 days

End point values	Arm A: ATRA	Arm B: GO+ATRA	Safety population
Number of subjects analysed	295	290	585
Units: Rate
number (confidence interval 95%)	0.05 (0.03 to 0.08)	0.08 (0.05 to 0.11)	0.07 (0.05 to 0.09)

No statistical analyses for this end point

Secondary: Hematological recovery induction cycle 1

Top of page

End point title

Hematological recovery induction cycle 1

End point description

In the first induction cycle, there were no major differences between the two treatment arms regarding hematological recovery of neutrophils and platelets. Arm A: ATRA Arm B: GO + ATRA N=298 N=287 Component Time [days] Rate 95% CI Rate 95% CI ANC recovery (> 0.5 G/l) 28 0.59 (0.53, 0.65) 0.61 (0.55, 0.67) ANC recovery (> 1.5 G/l) 28 0.37 (0.31, 0.43) 0.36 (0.3, 0.43) Platelet recovery (> 20 G/l) 28 0.80 (0.75, 0.85) 0.80 (0.74, 0.84) Platelet recovery (> 50 G/l) 28 0.74 (0.69, 0.8) 0.69 (0.63, 0.74) Platelet recovery (> 100 G/l) 28 0.62 (0.56, 0.68) 0.57 (0.51, 0.64)

End point type

Secondary

End point timeframe

Induction cycle 1

End point values	Safety population
Number of subjects analysed	585
Units: Recovery rates
number (not applicable)	0

Attachments

Recovery of neutrophils_induction 1
Recovery of platelets_induction 1

No statistical analyses for this end point

Secondary: Hematological recovery induction cycle 2

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End point title

Hematological recovery induction cycle 2

End point description

Recovery rates of platelets >20 G/l, >50 G/l and >100 G/l at day 28 were remarkably lower in the investigational arm (GO+ATRA) (0.55, 0.39 and 0.25) compared to the standard arm (ATRA) (0.76, 0.63 and 0.49). Arm A: ATRA Arm B: GO + ATRA N=274 N=223 Component Time [days] Rate 95% CI Rate 95% CI ANC recovery (> 0.5 G/l) 28 0.67 (0.61, 0.73) 0.60 (0.53, 0.67) ANC recovery (> 1.5 G/l) 28 0.42 (0.36, 0.49) 0.38 (0.32, 0.46) Platelet recovery (> 20 G/l) 28 0.76 (0.7, 0.81) 0.55 (0.48, 0.62) Platelet recovery (> 50 G/l) 28 0.63 (0.57, 0.7) 0.39 (0.32, 0.46) Platelet recovery (> 100 G/l) 28 0.49 (0.43, 0.56) 0.25 (0.19, 0.32)

End point type

Secondary

End point timeframe

Induction cycle 2

End point values	Safety population
Number of subjects analysed	585
Units: Rate of recovery
number (not applicable)	0

Attachments

Recovery of neutrophils_induction 2
Recovery of platelets_induction 2

No statistical analyses for this end point

Secondary: Hematological recovery consolidation cycle 1

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End point title

Hematological recovery consolidation cycle 1

End point description

Recovery rates of platelets >20 G/l, >50 G/l and >100 G/l at day 28 were remarkably lower in the investigational arm (GO+ATRA) (0.57, 0.38 and 0.23) compared to the standard arm (ATRA) (0.77, 0.55 and 0.33). Arm A: ATRA Arm B: GO + ATRA N=268 N=180 Component Time [days] Rate 95% CI Rate 95% CI ANC recovery (> 0.5 G/l) 28 0.87 (0.82, 0.91) 0.83 (0.76, 0.88) ANC recovery (> 1.5 G/l) 28 0.70 (0.64, 0.76) 0.68 (0.6, 0.76) Platelet recovery (> 20 G/l) 28 0.77 (0.71, 0.83) 0.57 (0.49, 0.65) Platelet recovery (> 50 G/l) 28 0.55 (0.48, 0.62) 0.38 (0.3, 0.46) Platelet recovery (> 100 G/l) 28 0.33 (0.27, 0.4) 0.23 (0.17, 0.31)

End point type

Secondary

End point timeframe

Consolidation cycle 1

End point values	Safety population
Number of subjects analysed	585
Units: Rate of recovery
number (not applicable)	0

Attachments

Recovery of platelets_consolidation 1
Recovery of neutrophils_consolidation 1

No statistical analyses for this end point

Secondary: Hematological recovery consolidation cycle 2

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End point title

Hematological recovery consolidation cycle 2

End point description

In the second consolidation cycle, there were no major differences between the two treatment arms regarding the hematological recovery of neutrophils and platelets. Arm A: ATRA Arm B: GO + ATRA N=249 N=158 Component Time [days] Rate 95% CI Rate 95% CI ANC recovery (> 0.5 G/l) 28 0.89 (0.84, 0.93) 0.87 (0.8, 0.92) ANC recovery (> 1.5 G/l) 28 0.75 (0.69, 0.81) 0.77 (0.69, 0.84) Platelet recovery (> 20 G/l) 28 0.73 (0.66, 0.79) 0.67 (0.59, 0.75) Platelet recovery (> 50 G/l) 28 0.50 (0.43, 0.57) 0.43 (0.35, 0.52) Platelet recovery (> 100 G/l) 28 0.27 (0.21, 0.34) 0.25 (0.19, 0.34)

End point type

Secondary

End point timeframe

Consolidation cycle 2

End point values	Safety population
Number of subjects analysed	585
Units: Rates of recovery
number (not applicable)	0

Attachments

Recovery of neutrophils_consolidation 2
Recovery of platelets_consolidation 2

No statistical analyses for this end point

Secondary: Hematological recovery consolidation cycle 3

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End point title

Hematological recovery consolidation cycle 3

End point description

In the third consolidation cycle, there were no major differences between the two treatment arms regarding the hematological recovery of neutrophils and platelets. Arm A: ATRA Arm B: GO + ATRA N=225 N=143 Component Time [days] Rate 95% CI Rate 95% CI ANC recovery (> 0.5 G/l) 28 0.90 (0.85, 0.94) 0.85 (0.78, 0.91) ANC recovery (> 1.5 G/l) 28 0.74 (0.67, 0.8) 0.77 (0.68, 0.84) Platelet recovery (> 20 G/l) 28 0.78 (0.71, 0.84) 0.67 (0.57, 0.76) Platelet recovery (> 50 G/l) 28 0.51 (0.43, 0.59) 0.49 (0.39, 0.59) Platelet recovery (> 100 G/l) 28 0.36 (0.29, 0.45) 0.27 (0.19, 0.37)

End point type

Secondary

End point timeframe

Consolidation cycle 3

End point values	Safety population
Number of subjects analysed	585
Units: Rates of recovery
number (not applicable)	0

Attachments

Recovery of neutrophils_consolidation 3
Recovery of platelets_consolidation 3

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

The adverse event reporting period began upon signing of informed consent and ended 28 days after the last treatment administration or until all drug-related toxicities were resolved, or until the Investigators assessed AEs as chronic or stable.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.1

Reporting group title

Arm A: ATRA

Reporting group description

Reporting group title

Arm B: GO+ATRA

Reporting group description

Serious adverse events	Arm A: ATRA	Arm B: GO+ATRA
Total subjects affected by serious adverse events
subjects affected / exposed	125 / 295 (42.37%)	160 / 290 (55.17%)
number of deaths (all causes)	21	36
number of deaths resulting from adverse events	21	36
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatic neoplasm
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Haemorrhage
subjects affected / exposed	1 / 295 (0.34%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	1 / 1	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Infarction
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombophlebitis
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Venoocclusive disease
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Appendicectomy
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colon operation
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 295 (0.00%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	7 / 295 (2.37%)	10 / 290 (3.45%)
occurrences causally related to treatment / all	7 / 8	8 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden death
subjects affected / exposed	2 / 295 (0.68%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Anaphylactic shock
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cytokine release syndrome
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	1 / 295 (0.34%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vaginal haemorrhage
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	1 / 295 (0.34%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchostenosis
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 295 (0.34%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 295 (0.00%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infiltration
subjects affected / exposed	1 / 295 (0.34%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 295 (0.34%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Pneumonitis
subjects affected / exposed	2 / 295 (0.68%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 295 (0.34%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	1 / 295 (0.34%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	2 / 2
Pulmonary infarction
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	2 / 295 (0.68%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 295 (0.34%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Sputum discoloured
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Depression
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Blood bilirubin
subjects affected / exposed	2 / 295 (0.68%)	4 / 290 (1.38%)
occurrences causally related to treatment / all	3 / 3	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Blood creatinine
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gamma-glutamyltransferase
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Glomerular filtration rate
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoglobin
subjects affected / exposed	8 / 295 (2.71%)	9 / 290 (3.10%)
occurrences causally related to treatment / all	9 / 10	19 / 19
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutrophil count
subjects affected / exposed	1 / 295 (0.34%)	3 / 290 (1.03%)
occurrences causally related to treatment / all	0 / 1	8 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	10 / 295 (3.39%)	21 / 290 (7.24%)
occurrences causally related to treatment / all	21 / 22	45 / 45
deaths causally related to treatment / all	0 / 0	0 / 0
Troponin T increased
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Arterial injury
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Arrhythmia supraventricular
subjects affected / exposed	1 / 295 (0.34%)	3 / 290 (1.03%)
occurrences causally related to treatment / all	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 295 (0.34%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Atrioventricular block
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	2 / 295 (0.68%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Cardiac failure
subjects affected / exposed	0 / 295 (0.00%)	3 / 290 (1.03%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiomyopathy
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiovascular insufficiency
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Electrocardiogram QT prolonged
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
subjects affected / exposed	2 / 295 (0.68%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	2 / 295 (0.68%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	1 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 295 (0.00%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocarditis
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tachyarrhythmia
subjects affected / exposed	1 / 295 (0.34%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Central nervous system lesion
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	3 / 295 (1.02%)	6 / 290 (2.07%)
occurrences causally related to treatment / all	1 / 3	3 / 6
deaths causally related to treatment / all	0 / 1	1 / 2
Cerebrovascular accident
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 295 (0.34%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dyskinesia
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neurotoxicity
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Paralysis
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 295 (0.00%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Speech disorder
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 295 (0.00%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Aplastic anaemia
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bone marrow disorder
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bone marrow failure
subjects affected / exposed	1 / 295 (0.34%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	15 / 295 (5.08%)	24 / 290 (8.28%)
occurrences causally related to treatment / all	18 / 21	24 / 33
deaths causally related to treatment / all	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	12 / 295 (4.07%)	10 / 290 (3.45%)
occurrences causally related to treatment / all	19 / 20	25 / 25
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 295 (0.34%)	3 / 290 (1.03%)
occurrences causally related to treatment / all	1 / 1	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Vision blurred
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	3 / 295 (1.02%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anal fistula
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anal ulcer
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	2 / 295 (0.68%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 295 (0.00%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Enteritis
subjects affected / exposed	2 / 295 (0.68%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis haemorrhagic
subjects affected / exposed	1 / 295 (0.34%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroduodenal haemorrhage
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal inflammation
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gingival bleeding
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gingivitis ulcerative
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
subjects affected / exposed	4 / 295 (1.36%)	6 / 290 (2.07%)
occurrences causally related to treatment / all	1 / 4	3 / 6
deaths causally related to treatment / all	0 / 1	0 / 0
Intra-abdominal haemorrhage
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intussusception
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Lip swelling
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic colitis
subjects affected / exposed	2 / 295 (0.68%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	1 / 1
Oral pain
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal tenesmus
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 295 (0.00%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 295 (0.34%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 295 (0.00%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	0 / 295 (0.00%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic steatosis
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis toxic
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Hepatorenal syndrome
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Venoocclusive liver disease
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Drug eruption
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rash
subjects affected / exposed	1 / 295 (0.34%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	2 / 295 (0.68%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Renal disorder
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	1 / 295 (0.34%)	4 / 290 (1.38%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 2
Renal injury
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bone pain
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Joint swelling
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal disorder
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Polyarthritis
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue necrosis
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abscess
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anal infection
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	2 / 295 (0.68%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	2 / 295 (0.68%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchopulmonary aspergillosis
subjects affected / exposed	2 / 295 (0.68%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cellulitis
subjects affected / exposed	0 / 295 (0.00%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridial infection
subjects affected / exposed	1 / 295 (0.34%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium colitis
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea infectious
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterococcal infection
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fungal infection
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
H1N1 influenza
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Infection
subjects affected / exposed	4 / 295 (1.36%)	3 / 290 (1.03%)
occurrences causally related to treatment / all	1 / 4	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 295 (0.34%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Muscle abscess
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic infection
subjects affected / exposed	4 / 295 (1.36%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	4 / 4	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Opportunistic infection
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Orchitis
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Parainfluenzae virus infection
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	23 / 295 (7.80%)	33 / 290 (11.38%)
occurrences causally related to treatment / all	15 / 33	22 / 37
deaths causally related to treatment / all	1 / 4	2 / 4
Pseudomonas infection
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulpitis dental
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Purulent pericarditis
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	3 / 295 (1.02%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	28 / 295 (9.49%)	46 / 290 (15.86%)
occurrences causally related to treatment / all	20 / 29	30 / 54
deaths causally related to treatment / all	6 / 8	8 / 16
Septic shock
subjects affected / exposed	0 / 295 (0.00%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Skin infection
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	2 / 295 (0.68%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	3 / 3	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	1 / 295 (0.34%)	0 / 290 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tooth infection
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tubo-ovarian abscess
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 295 (0.68%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 295 (0.00%)	1 / 290 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour lysis syndrome
subjects affected / exposed	0 / 295 (0.00%)	2 / 290 (0.69%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 3%

Non-serious adverse events	Arm A: ATRA	Arm B: GO+ATRA
Total subjects affected by non serious adverse events
subjects affected / exposed	295 / 295 (100.00%)	290 / 290 (100.00%)
Vascular disorders
Haematoma
subjects affected / exposed	25 / 295 (8.47%)	36 / 290 (12.41%)
occurrences all number	50	52
Haemorrhage
subjects affected / exposed	11 / 295 (3.73%)	7 / 290 (2.41%)
occurrences all number	17	7
Phlebitis
subjects affected / exposed	44 / 295 (14.92%)	41 / 290 (14.14%)
occurrences all number	59	47
Thrombosis
subjects affected / exposed	25 / 295 (8.47%)	14 / 290 (4.83%)
occurrences all number	36	29
General disorders and administration site conditions
Chills
subjects affected / exposed	23 / 295 (7.80%)	62 / 290 (21.38%)
occurrences all number	39	103
Fatigue
subjects affected / exposed	83 / 295 (28.14%)	92 / 290 (31.72%)
occurrences all number	193	198
Hyperhidrosis
subjects affected / exposed	17 / 295 (5.76%)	14 / 290 (4.83%)
occurrences all number	32	18
Injection site reaction
subjects affected / exposed	61 / 295 (20.68%)	71 / 290 (24.48%)
occurrences all number	120	158
Pain
subjects affected / exposed	81 / 295 (27.46%)	53 / 290 (18.28%)
occurrences all number	128	80
Pyrexia
subjects affected / exposed	173 / 295 (58.64%)	173 / 290 (59.66%)
occurrences all number	416	448
Immune system disorders
Hypersensitivity
subjects affected / exposed	59 / 295 (20.00%)	68 / 290 (23.45%)
occurrences all number	90	110
Respiratory, thoracic and mediastinal disorders
Chest pain
subjects affected / exposed	19 / 295 (6.44%)	24 / 290 (8.28%)
occurrences all number	31	30
Cough
subjects affected / exposed	64 / 295 (21.69%)	65 / 290 (22.41%)
occurrences all number	82	95
Dyspnoea
subjects affected / exposed	45 / 295 (15.25%)	50 / 290 (17.24%)
occurrences all number	60	63
Oropharyngeal pain
subjects affected / exposed	34 / 295 (11.53%)	32 / 290 (11.03%)
occurrences all number	44	40
Pleural effusion
subjects affected / exposed	12 / 295 (4.07%)	19 / 290 (6.55%)
occurrences all number	18	23
Pneumonitis
subjects affected / exposed	15 / 295 (5.08%)	14 / 290 (4.83%)
occurrences all number	17	16
Pulmonary haemorrhage
subjects affected / exposed	76 / 295 (25.76%)	87 / 290 (30.00%)
occurrences all number	120	174
Psychiatric disorders
Agitation
subjects affected / exposed	33 / 295 (11.19%)	32 / 290 (11.03%)
occurrences all number	44	52
Anxiety
subjects affected / exposed	25 / 295 (8.47%)	22 / 290 (7.59%)
occurrences all number	44	27
Confusional state
subjects affected / exposed	18 / 295 (6.10%)	17 / 290 (5.86%)
occurrences all number	23	24
Depression
subjects affected / exposed	22 / 295 (7.46%)	33 / 290 (11.38%)
occurrences all number	45	54
Insomnia
subjects affected / exposed	92 / 295 (31.19%)	107 / 290 (36.90%)
occurrences all number	213	230
Investigations
Alanine aminotransferase
subjects affected / exposed	26 / 295 (8.81%)	34 / 290 (11.72%)
occurrences all number	59	53
Aspartate aminotransferase
subjects affected / exposed	22 / 295 (7.46%)	37 / 290 (12.76%)
occurrences all number	40	60
Blood alkaline phosphatase
subjects affected / exposed	11 / 295 (3.73%)	16 / 290 (5.52%)
occurrences all number	19	34
Blood bilirubin
subjects affected / exposed	20 / 295 (6.78%)	26 / 290 (8.97%)
occurrences all number	26	29
Blood creatine
subjects affected / exposed	5 / 295 (1.69%)	24 / 290 (8.28%)
occurrences all number	15	42
Blood lactate dehydrogenase increased
subjects affected / exposed	8 / 295 (2.71%)	11 / 290 (3.79%)
occurrences all number	18	22
C-reactive protein increased
subjects affected / exposed	73 / 295 (24.75%)	60 / 290 (20.69%)
occurrences all number	160	137
Gamma-glutamyltransferase
subjects affected / exposed	36 / 295 (12.20%)	49 / 290 (16.90%)
occurrences all number	76	99
General physical condition
subjects affected / exposed	18 / 295 (6.10%)	24 / 290 (8.28%)
occurrences all number	20	27
Haemoglobin
subjects affected / exposed	260 / 295 (88.14%)	255 / 290 (87.93%)
occurrences all number	1092	981
Neutrophil count
subjects affected / exposed	124 / 295 (42.03%)	120 / 290 (41.38%)
occurrences all number	403	358
Platelet count decreased
subjects affected / exposed	262 / 295 (88.81%)	254 / 290 (87.59%)
occurrences all number	1029	979
Prothrombin time prolonged
subjects affected / exposed	14 / 295 (4.75%)	17 / 290 (5.86%)
occurrences all number	19	21
Weight increased
subjects affected / exposed	47 / 295 (15.93%)	52 / 290 (17.93%)
occurrences all number	90	101
Cardiac disorders
Arrhythmia supraventricular
subjects affected / exposed	44 / 295 (14.92%)	41 / 290 (14.14%)
occurrences all number	70	70
Hypertension
subjects affected / exposed	66 / 295 (22.37%)	84 / 290 (28.97%)
occurrences all number	113	161
Hypotension
subjects affected / exposed	27 / 295 (9.15%)	32 / 290 (11.03%)
occurrences all number	44	48
Nervous system disorders
Dizziness
subjects affected / exposed	47 / 295 (15.93%)	51 / 290 (17.59%)
occurrences all number	78	102
Headache
subjects affected / exposed	92 / 295 (31.19%)	116 / 290 (40.00%)
occurrences all number	188	272
Syncope
subjects affected / exposed	19 / 295 (6.44%)	18 / 290 (6.21%)
occurrences all number	23	27
Blood and lymphatic system disorders
Coagulopathy
subjects affected / exposed	7 / 295 (2.37%)	14 / 290 (4.83%)
occurrences all number	8	18
Febrile neutropenia
subjects affected / exposed	124 / 295 (42.03%)	131 / 290 (45.17%)
occurrences all number	194	255
Leukopenia
subjects affected / exposed	230 / 295 (77.97%)	217 / 290 (74.83%)
occurrences all number	915	826
Lymphopenia
subjects affected / exposed	13 / 295 (4.41%)	15 / 290 (5.17%)
occurrences all number	45	42
Eye disorders
Dry eye
subjects affected / exposed	17 / 295 (5.76%)	10 / 290 (3.45%)
occurrences all number	21	14
Eye haemorrhage
subjects affected / exposed	9 / 295 (3.05%)	20 / 290 (6.90%)
occurrences all number	11	28
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	72 / 295 (24.41%)	84 / 290 (28.97%)
occurrences all number	99	114
Abdominal pain upper
subjects affected / exposed	43 / 295 (14.58%)	43 / 290 (14.83%)
occurrences all number	62	66
Colitis
subjects affected / exposed	24 / 295 (8.14%)	30 / 290 (10.34%)
occurrences all number	34	34
Constipation
subjects affected / exposed	115 / 295 (38.98%)	113 / 290 (38.97%)
occurrences all number	257	233
Diarrhoea
subjects affected / exposed	158 / 295 (53.56%)	150 / 290 (51.72%)
occurrences all number	266	243
Dyspepsia
subjects affected / exposed	25 / 295 (8.47%)	24 / 290 (8.28%)
occurrences all number	31	30
Enteritis
subjects affected / exposed	8 / 295 (2.71%)	10 / 290 (3.45%)
occurrences all number	8	12
Flatulence
subjects affected / exposed	21 / 295 (7.12%)	23 / 290 (7.93%)
occurrences all number	27	34
Gastric haemorrhage
subjects affected / exposed	23 / 295 (7.80%)	46 / 290 (15.86%)
occurrences all number	25	73
Gastrointestinal inflammation
subjects affected / exposed	137 / 295 (46.44%)	145 / 290 (50.00%)
occurrences all number	214	277
Haemorrhoids
subjects affected / exposed	17 / 295 (5.76%)	19 / 290 (6.55%)
occurrences all number	24	26
Nausea
subjects affected / exposed	179 / 295 (60.68%)	197 / 290 (67.93%)
occurrences all number	405	499
Oral pain
subjects affected / exposed	12 / 295 (4.07%)	11 / 290 (3.79%)
occurrences all number	13	12
Proctalgia
subjects affected / exposed	20 / 295 (6.78%)	17 / 290 (5.86%)
occurrences all number	24	22
Toothache
subjects affected / exposed	11 / 295 (3.73%)	12 / 290 (4.14%)
occurrences all number	13	12
Vomiting
subjects affected / exposed	50 / 295 (16.95%)	102 / 290 (35.17%)
occurrences all number	97	245
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	16 / 295 (5.42%)	22 / 290 (7.59%)
occurrences all number	25	37
Dry skin
subjects affected / exposed	17 / 295 (5.76%)	21 / 290 (7.24%)
occurrences all number	20	28
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	10 / 295 (3.39%)	17 / 290 (5.86%)
occurrences all number	16	28
Petechiae
subjects affected / exposed	53 / 295 (17.97%)	72 / 290 (24.83%)
occurrences all number	109	140
Pruritus
subjects affected / exposed	46 / 295 (15.59%)	25 / 290 (8.62%)
occurrences all number	63	39
Rash
subjects affected / exposed	110 / 295 (37.29%)	103 / 290 (35.52%)
occurrences all number	210	182
Skin lesion
subjects affected / exposed	14 / 295 (4.75%)	22 / 290 (7.59%)
occurrences all number	17	30
Renal and urinary disorders
Fluid retention
subjects affected / exposed	131 / 295 (44.41%)	125 / 290 (43.10%)
occurrences all number	262	275
Haemorrhage urinary tract
subjects affected / exposed	22 / 295 (7.46%)	28 / 290 (9.66%)
occurrences all number	27	39
Renal failure
subjects affected / exposed	9 / 295 (3.05%)	10 / 290 (3.45%)
occurrences all number	9	13
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	31 / 295 (10.51%)	30 / 290 (10.34%)
occurrences all number	41	44
Back pain
subjects affected / exposed	59 / 295 (20.00%)	53 / 290 (18.28%)
occurrences all number	97	73
Bone pain
subjects affected / exposed	40 / 295 (13.56%)	33 / 290 (11.38%)
occurrences all number	63	47
Myalgia
subjects affected / exposed	15 / 295 (5.08%)	13 / 290 (4.48%)
occurrences all number	21	15
Neck pain
subjects affected / exposed	12 / 295 (4.07%)	15 / 290 (5.17%)
occurrences all number	13	15
Pain in extremity
subjects affected / exposed	28 / 295 (9.49%)	31 / 290 (10.69%)
occurrences all number	35	41
Infections and infestations
Anal infection
subjects affected / exposed	10 / 295 (3.39%)	11 / 290 (3.79%)
occurrences all number	14	15
Cellulitis
subjects affected / exposed	28 / 295 (9.49%)	35 / 290 (12.07%)
occurrences all number	34	40
Device related infection
subjects affected / exposed	33 / 295 (11.19%)	39 / 290 (13.45%)
occurrences all number	45	50
Enterococcal infection
subjects affected / exposed	11 / 295 (3.73%)	15 / 290 (5.17%)
occurrences all number	30	29
Enterocolitis infectious
subjects affected / exposed	15 / 295 (5.08%)	9 / 290 (3.10%)
occurrences all number	23	11
Fungal infection
subjects affected / exposed	11 / 295 (3.73%)	12 / 290 (4.14%)
occurrences all number	13	14
Gingivitis
subjects affected / exposed	9 / 295 (3.05%)	9 / 290 (3.10%)
occurrences all number	13	10
Herpes virus infection
subjects affected / exposed	19 / 295 (6.44%)	23 / 290 (7.93%)
occurrences all number	24	26
Infection
subjects affected / exposed	53 / 295 (17.97%)	42 / 290 (14.48%)
occurrences all number	89	61
Lip infection
subjects affected / exposed	31 / 295 (10.51%)	23 / 290 (7.93%)
occurrences all number	42	31
Pharyngitis
subjects affected / exposed	7 / 295 (2.37%)	13 / 290 (4.48%)
occurrences all number	14	14
Pneumonia
subjects affected / exposed	74 / 295 (25.08%)	79 / 290 (27.24%)
occurrences all number	104	112
Rhinitis
subjects affected / exposed	8 / 295 (2.71%)	12 / 290 (4.14%)
occurrences all number	10	18
Sepsis
subjects affected / exposed	76 / 295 (25.76%)	84 / 290 (28.97%)
occurrences all number	101	124
Staphylococcal infection
subjects affected / exposed	10 / 295 (3.39%)	92 / 290 (31.72%)
occurrences all number	10	12
Urinary tract infection
subjects affected / exposed	24 / 295 (8.14%)	29 / 290 (10.00%)
occurrences all number	29	35
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	43 / 295 (14.58%)	51 / 290 (17.59%)
occurrences all number	66	82
Hyperglycaemia
subjects affected / exposed	16 / 295 (5.42%)	19 / 290 (6.55%)
occurrences all number	20	24
Hyperkalaemia
subjects affected / exposed	9 / 295 (3.05%)	10 / 290 (3.45%)
occurrences all number	10	11
Hyperuricaemia
subjects affected / exposed	23 / 295 (7.80%)	22 / 290 (7.59%)
occurrences all number	32	39
Hypoalbuminaemia
subjects affected / exposed	17 / 295 (5.76%)	22 / 290 (7.59%)
occurrences all number	20	29
Hypocalcaemia
subjects affected / exposed	26 / 295 (8.81%)	26 / 290 (8.97%)
occurrences all number	33	29
Hypokalaemia
subjects affected / exposed	150 / 295 (50.85%)	180 / 290 (62.07%)
occurrences all number	336	439
Hypomagnesaemia
subjects affected / exposed	13 / 295 (4.41%)	27 / 290 (9.31%)
occurrences all number	19	39

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Were there any global substantial amendments to the protocol? Yes

29 Jun 2010

Amendment No. 1 (dated 29 June 2010) to the protocol was issued after 5 patients were enrolled. The following major procedural changes (not all-inclusive) were made to the protocol: • Pfizer Pharma GmbH had become the legal successor of Wyeth Pharma GmbH • Implementation of the withdrawal of the market approval of gemtuzumab ozogamicin in the USA in June 2010 • Adaption and extension of reporting responsibilities regarding drug-associated risks and other reportable events

13 Apr 2012

Amendment No. 2 (dated 13 April 2012) to the protocol was issued after 141 patients were enrolled. The following major procedural changes (not all-inclusive) were made to the protocol: • Implementation of dose reduction of cytarabine, etoposide and idarubicin in the second induction cycle (urgent amendment on 23 December 2011) due to increased rates of prolonged thrombocytopenia and neutropenia and corresponding increased rates of severe infections detected within the continuous safety assessment • Addition of new information regarding measurable residual disease (MRD) and implementation of the option to perform an allogeneic HCT after consolidation cycle 2 or 3 in patients with persistently high MRD values

19 Jun 2012

Amendment No. 3 (dated 19 June 2012) to the protocol was issued after 154 patients were enrolled. The following major procedural changes (not all-inclusive) were made to the protocol: • Implementation of instructions regarding the concominant administration of antimycotic prophylaxis with azoles and definition of re-start of azoles for day 6 of second induction cycle (urgent amendment on 27 April 2012)

31 Oct 2013

Amendment No. 4 (dated 31 October 2013) to the protocol was issued after 295 patients were enrolled. The following major procedural changes (not all-inclusive) were made to the protocol: • Increase of sample size from 276 to 588 patients • Addition of OS as second primary endpoint • Integration of new information regarding capillary leak syndrome with Pegfilgrastim from June 2013 • Integration of new information from investigator’s brochure of gemtuzumab ozogamicin from June 2013

10 Nov 2016

Amendment No. 5 (dated 10 November 2016) to the protocol was issued after 520 patients were enrolled. The following major procedural changes (not all-inclusive) were made to the protocol: • Change of coordinating investigator from Prof. Richard Schlenk to Prof. Hartmut Döhner • Integration of urgent amendment from 07 June 2016 for the investigational arm: In case of prolonged thrombocytopenia grade 3/4 > day 35 during induction therapy, gemtuzumab ozogamicin will not be administered in the subsequent treatment cycles.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
01 Jun 2010	First interruption was performed due to with-drawal of marketing authorization for gemtuzumab ozogamicin and the associated need for a protocol and ICF amendment.	14 Oct 2010
22 Dec 2011	Second interruption took place due to implementation of dose reduction of cytarabine, etoposide and idarubicin in the second induction cycle (urgent amendment on 23 December 2011) due to increased rates of prolonged throm-bocytopenia and neutropenia and corresponding increased rates of severe infections detected within the continuous safety assessment.	23 Apr 2012
27 Sep 2013	The third interruption took place due to achievement of recruitment goals until the protocol amendment with the increase of sample size (from n=276 to n=588 patients), change of primary study endpoint (from EFS to OS), integration of new information regarding capillary leak syndrome with pegfilgrastim from June 2013 and integration of new information from investigator’s brochure of gemtuzumab ozogamicin from June 2013 was approved.	20 Dec 2013

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/31851556
http://www.ncbi.nlm.nih.gov/pubmed/33367545

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Clinical trials

Clinical Trial Results: Phase III study of chemotherapy in combination with ATRA with or without gemtuzumab ozogamicin in patients with acute myeloid leukemia and NPM1 gene mutation

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Overall Survival

Primary: Overall Survival

Secondary: Event-free survival (original definition, ELN 2017)

Secondary: Event-free survival (original definition, ELN 2017)

Secondary: Event-free survival (ELN 2022)

Secondary: Event-free survival (ELN 2022)

Secondary: Rate of CR

Secondary: Rate of CR

Secondary: Rate of CR/CRi

Secondary: Rate of CR/CRi

Secondary: Rate of CR/CRh

Secondary: Rate of CR/CRh

Secondary: Cumulative incidence of relapse

Secondary: Cumulative incidence of relapse

Secondary: Cumulative incidence of death

Secondary: Cumulative incidence of death

Secondary: 30-day mortality

Secondary: 30-day mortality

Secondary: 60-day mortality

Secondary: 60-day mortality

Secondary: Hematological recovery induction cycle 1

Secondary: Hematological recovery induction cycle 1

Secondary: Hematological recovery induction cycle 2

Secondary: Hematological recovery induction cycle 2

Secondary: Hematological recovery consolidation cycle 1

Secondary: Hematological recovery consolidation cycle 1

Secondary: Hematological recovery consolidation cycle 2

Secondary: Hematological recovery consolidation cycle 2

Secondary: Hematological recovery consolidation cycle 3

Secondary: Hematological recovery consolidation cycle 3

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

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Clinical Trial Results:
Phase III study of chemotherapy in combination with ATRA with or without gemtuzumab ozogamicin in patients with acute myeloid leukemia and NPM1 gene mutation