NCT03268954 · OUTCOME

Time to Acute Myelogenous Leukemia (AML) Transformation in Higher-Risk Myelodysplastic Syndromes (HR MDS), Higher-Risk Chronic Myelomonocytic Leukemias (HR CMML) and HR MDS/CMML Participants

Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML), or Low-Blast Acute Myelogenous Leukemia (AML) · Source last updated 2025-10-29

Results reported by the registry submitting party. Population, time horizon, units and missing values must be read together.

Measure: MEDIAN
Unit: months
Interval / dispersion: 95% Confidence Interval
Time frame: From randomization until transformation to AML (up to approximately 42 months)

What was measured

Time to AML transformation in HR MDS and CMML participants was defined as time from randomization to documented AML transformation as determined by the independent review committee (IRC) assessment. Participants who died before progression to AML were censored. Transformation to AML was defined, according to WHO classification, as a participant having 20% blasts in the blood or marrow and increase of blast count by 50%.

Analysis population: ITT Population included all participants who were randomized. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis for the given category.

Groups in this outcome

Azacitidine 75 mg/m^2

Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.

Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2

Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.

Group identifiers and denominators belong to this outcome only. They may differ in another outcome or in safety reporting.

Analysis denominator · Participants

Group	Source count
Azacitidine 75 mg/m^2	174
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	177

Reported measurements

HR MDS Participants

Analysis denominator · Participants

Group	Source count
Azacitidine 75 mg/m^2	163
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	161

Values in months · Interval/dispersion: 95% Confidence Interval
Group	Value	Spread	Lower	Upper	Comment
Azacitidine 75 mg/m^2	35.6	Not reported	26.51	NA	The upper limit of 95% confidence interval (CI) was not estimable due to low number of participants with event.
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	NA	Not reported	23.29	NA	The median, and upper limit of 95% CI were not estimable due to low number of participants with event.

HR CMML Participants

Analysis denominator · Participants

Group	Source count
Azacitidine 75 mg/m^2	11
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	16

Values in months · Interval/dispersion: 95% Confidence Interval
Group	Value	Spread	Lower	Upper	Comment
Azacitidine 75 mg/m^2	NA	Not reported	NA	NA	The median, lower limit, and upper limit of 95% CI were not estimable due to low number of participants with event.
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	NA	Not reported	NA	NA	The median, lower limit, and upper limit of 95% CI were not estimable due to low number of participants with event.

HR MDS/CMML Participants

Analysis denominator · Participants

Group	Source count
Azacitidine 75 mg/m^2	174
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	177

Values in months · Interval/dispersion: 95% Confidence Interval
Group	Value	Spread	Lower	Upper	Comment
Azacitidine 75 mg/m^2	35.6	Not reported	29.04	NA	The upper limit of 95% CI was not estimable due to low number of participants with event.
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	NA	Not reported	24.28	NA	The median, and upper limit of 95% CI were not estimable due to low number of participants with event.

Source statistical analyses

Group order, estimate direction, methods and comments are retained. No treatment ranking is inferred.

ci Lower Limit
0.660
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
1.630
estimate Comment
HR:unadjusted stratified Cox proportional HazardRegression with stratification(IPSS-R risk groups=very high,high,or intermediate for HRMDS/CMML),treatment as factor.HR\<1:better prevention of AML transformation in combination arm than azacitidine arm.
group Description
Time to AML Transformation in HR MDS Participants
group Ids
OG000
OG001
non Inferiority Type
SUPERIORITY
p Value
=0.562
p Value Comment
P-value comparing time to AML Transformation between treatment groups was based on 1-sided stratified log-rank test stratified by IPSS-R risk groups of very high, high, or intermediate for HR MDS.
param Type
Hazard Ratio (HR)
param Value
1.037
statistical Method
Log Rank
ci Lower Limit
0.068
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
33.773
estimate Comment
HR:unadjusted stratified Cox proportional HazardRegression with stratification(IPSS-R risk groups=very high,high,or intermediate for HRMDS/CMML),treatment as factor.HR\<1:better prevention of AML transformation in combination arm than azacitidine arm.
group Description
Time to AML Transformation in HR CMML Participants
group Ids
OG000
OG001
non Inferiority Type
SUPERIORITY
p Value
=0.603
p Value Comment
P-value comparing time to AML Transformation between treatment groups was based on 1-sided stratified log-rank test stratified by IPSS-R risk groups of very high, high, or intermediate for HR CMML.
param Type
Hazard Ratio (HR)
param Value
1.512
statistical Method
Log Rank
ci Lower Limit
0.663
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
1.610
estimate Comment
HR:unadjusted stratified Cox proportional HazardRegression with stratification(IPSS-R risk groups=very high,high,or intermediate for HRMDS/CMML),treatment as factor.HR\<1:better prevention of AML transformation in combination arm than azacitidine arm.
group Description
Time to AML Transformation in HR MDS/CMML Participants
group Ids
OG000
OG001
non Inferiority Type
SUPERIORITY
p Value
=0.558
p Value Comment
P-value comparing time to AML Transformation between treatment groups was based on 1-sided stratified log-rank test stratified by IPSS-R risk groups of very high, high, or intermediate for HR CMML/MDS.
param Type
Hazard Ratio (HR)
param Value
1.034
statistical Method
Log Rank

Complete source fields

analyses

ci Lower Limit
0.660
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
1.630
estimate Comment
HR:unadjusted stratified Cox proportional HazardRegression with stratification(IPSS-R risk groups=very high,high,or intermediate for HRMDS/CMML),treatment as factor.HR\<1:better prevention of AML transformation in combination arm than azacitidine arm.
group Description
Time to AML Transformation in HR MDS Participants
group Ids
OG000
OG001
non Inferiority Type
SUPERIORITY
p Value
=0.562
p Value Comment
P-value comparing time to AML Transformation between treatment groups was based on 1-sided stratified log-rank test stratified by IPSS-R risk groups of very high, high, or intermediate for HR MDS.
param Type
Hazard Ratio (HR)
param Value
1.037
statistical Method
Log Rank
ci Lower Limit
0.068
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
33.773
estimate Comment
HR:unadjusted stratified Cox proportional HazardRegression with stratification(IPSS-R risk groups=very high,high,or intermediate for HRMDS/CMML),treatment as factor.HR\<1:better prevention of AML transformation in combination arm than azacitidine arm.
group Description
Time to AML Transformation in HR CMML Participants
group Ids
OG000
OG001
non Inferiority Type
SUPERIORITY
p Value
=0.603
p Value Comment
P-value comparing time to AML Transformation between treatment groups was based on 1-sided stratified log-rank test stratified by IPSS-R risk groups of very high, high, or intermediate for HR CMML.
param Type
Hazard Ratio (HR)
param Value
1.512
statistical Method
Log Rank
ci Lower Limit
0.663
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
1.610
estimate Comment
HR:unadjusted stratified Cox proportional HazardRegression with stratification(IPSS-R risk groups=very high,high,or intermediate for HRMDS/CMML),treatment as factor.HR\<1:better prevention of AML transformation in combination arm than azacitidine arm.
group Description
Time to AML Transformation in HR MDS/CMML Participants
group Ids
OG000
OG001
non Inferiority Type
SUPERIORITY
p Value
=0.558
p Value Comment
P-value comparing time to AML Transformation between treatment groups was based on 1-sided stratified log-rank test stratified by IPSS-R risk groups of very high, high, or intermediate for HR CMML/MDS.
param Type
Hazard Ratio (HR)
param Value
1.034
statistical Method
Log Rank

classes

categories
measurements
comment
The upper limit of 95% confidence interval (CI) was not estimable due to low number of participants with event.
group Id
OG000
lower Limit
26.51
upper Limit
NA
value
35.6
comment
The median, and upper limit of 95% CI were not estimable due to low number of participants with event.
group Id
OG001
lower Limit
23.29
upper Limit
NA
value
NA
denoms
counts
group Id
OG000
value
163
group Id
OG001
value
161
units
Participants
title
HR MDS Participants
categories
measurements
comment
The median, lower limit, and upper limit of 95% CI were not estimable due to low number of participants with event.
group Id
OG000
lower Limit
NA
upper Limit
NA
value
NA
comment
The median, lower limit, and upper limit of 95% CI were not estimable due to low number of participants with event.
group Id
OG001
lower Limit
NA
upper Limit
NA
value
NA
denoms
counts
group Id
OG000
value
11
group Id
OG001
value
16
units
Participants
title
HR CMML Participants
categories
measurements
comment
The upper limit of 95% CI was not estimable due to low number of participants with event.
group Id
OG000
lower Limit
29.04
upper Limit
NA
value
35.6
comment
The median, and upper limit of 95% CI were not estimable due to low number of participants with event.
group Id
OG001
lower Limit
24.28
upper Limit
NA
value
NA
denoms
counts
group Id
OG000
value
174
group Id
OG001
value
177
units
Participants
title
HR MDS/CMML Participants

denoms

counts
group Id
OG000
value
174
group Id
OG001
value
177
units
Participants

description

dispersion Type

95% Confidence Interval

groups

description
Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
id
OG000
title
Azacitidine 75 mg/m^2
description
Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
id
OG001
title
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2

param Type

MEDIAN

population Description

ITT Population included all participants who were randomized. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis for the given category.

reporting Status

POSTED

time Frame

From randomization until transformation to AML (up to approximately 42 months)

title

Time to Acute Myelogenous Leukemia (AML) Transformation in Higher-Risk Myelodysplastic Syndromes (HR MDS), Higher-Risk Chronic Myelomonocytic Leukemias (HR CMML) and HR MDS/CMML Participants

type

SECONDARY

unit Of Measure

months

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Preserved source evidence · Not medical advice