SURVIVAL OUTCOMES FROM THE QUAZAR AML-001 TRIAL WITH ORAL AZACITIDINE FOR PATIENTS WITH ACUTE MYELOID LEUKEMIA IN REMISSION BY DISEASE SUBTYPE, CYTOGENETIC RISK, AND NPM1 MUTATION STATUS AT DIAGNOSIS
Author(s): ,
Hartmut Döhner
Affiliations:
Universitätsklinikum Ulm,Ulm,Germany
,
Andrew Wei
Affiliations:
The Alfred Hospital,Melbourne,Australia;Monash University,Melbourne,Australia
,
Gail Roboz
Affiliations:
Weill Cornell Medicine,New York,United States;New York Presbyterian Hospital,New York,United States
,
Pau Montesinos
Affiliations:
Hospital Universitari i Politècnic La Fe,Valencia,Spain
,
Felicitas Thol
Affiliations:
Medizinische Hochschule Hannover,Hannover,Germany
,
Ignazia La Torre
Affiliations:
Celgene, a Bristol-Myers Squibb Company,Boudry,Switzerland
,
Barry Skikne
Affiliations:
University of Kansas Medical Center,Kansas City,United States;Bristol Myers Squibb,Princeton,United States
,
Wendy See
Affiliations:
Bristol Myers Squibb,Princeton,United States
,
Manuel Ugidos
Affiliations:
BMS Center for Innovation and Translational Research Europe (CITRE), a Bristol-Myers Squibb Company,Seville,Spain
,
Alberto Risueño
Affiliations:
BMS Center for Innovation and Translational Research Europe (CITRE), a Bristol-Myers Squibb Company,Seville,Spain
,
CL Beach
Affiliations:
Bristol Myers Squibb,Princeton,United States
Daniel Menezes
Affiliations:
Bristol Myers Squibb,Princeton,United States
EHA Library. Döhner H. 06/09/21; 324539; S131
Prof. Dr. Hartmut Döhner
Prof. Dr. Hartmut Döhner
Contributions
Abstract
Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S131

Type: Oral Presentation

Session title: AML classification

Background
Oral azacitidine (Oral-AZA; CC-486) is approved in the US for adult patients (pts) with acute myeloid leukemia (AML) who have achieved first complete remission (CR) or CR with incomplete blood count recovery (CRi) after intensive chemotherapy and are ineligible for intensive curative therapy. In the phase 3 QUAZAR trial, Oral-AZA significantly improved overall survival (OS) vs placebo (PBO) (median [med] 24.7 vs 14.8 months [mo], respectively; P<0.001). It has not been elucidated which subgroups of pts may derive greater benefit from Oral-AZA maintenance treatment (Tx) based on prognostic features or mutational profile.

Aims
Investigate the relationship between Oral-AZA and survival in post hoc analyses based on cytogenetic risk classification, AML subtype (de novo or secondary), and NPM1/FLT3 status at diagnosis (Dx).

Methods
Cytogenetic risk classification of intermediate- (int) and poor-risk pts was based on the 2012 NCCN Guidelines; pts with favorable risk were excluded. Pts were randomized 1:1 to Oral-AZA 300 mg or PBO within 4 mo of achieving first CR/CRi. Mutant (mut) or wild-type (WT) NPM1/FLT3-ITD status was determined at Dx. OS and relapse-free survival (RFS) were estimated using Kaplan-Meier methods. Cox Proportional Hazard Regression was used to obtain hazard ratios (HR; P values, Log-rank test). Measurable residual disease (MRD) analysis used a cutoff of ≥0.1% (P values, Fisher’s exact test).

Results
Of 472 randomized pts, 90.9% had de novo AML, and Oral-AZA provided a significant increase in med OS vs PBO (23.2 vs 14.6 mo; HR 0.73; P=0.0068) and RFS (10.2 vs 4.9 mo; HR 0.66; P=0.0002). For the underpowered pt group with secondary AML (n=43), there was a trend for increased OS with Oral-AZA vs PBO (28.2 vs 15.7 mo; HR 0.58; P=0.11) and significantly increased RFS (4.7 vs 2.4 mo; HR 0.47; P=0.0118). 86% of pts had int-risk cytogenetics, and within this population, OS was significantly increased with Oral-AZA vs PBO (25.4 vs 15.9 mo; HR 0.73; P=0.0093), as was RFS (11.0 vs 5.8 mo; HR 0.66; P=0.0004). The poor-risk cohort (14%; n=66), though underpowered, showed a trend for increased OS with Oral-AZA vs PBO (13.9 vs. 7.4 mo; HR 0.61; P=0.06), and RFS was similar (Oral-AZA 4.6 mo, PBO 3.7 mo; HR 0.63; P=0.08). Overall, 29.2% of pts had mutNPM1 at Dx (137/469), 9.8% (n=48) were FLT3-ITD positive, and 6% (n=30) had co-mutated NPM1/FLT3-ITD. In the PBO arm, mutNPM1 status vs WT was prognostically favorable for RFS (6.9 vs 4.6 mo; HR 0.64; P=0.0083) with a trend in increased OS (15.9 vs 14.6 mo; HR 0.75; P=0.10). Comparing treatment arms, the med OS for pts with mutNPM1 was considerably longer in the Oral-AZA arm vs PBO (46.1 vs 15.9 mo; HR 0.57; P=0.0138), and med RFS was significantly prolonged (23.2 vs 6.9 mo; HR 0.55; P=0.0098) (Figure). A larger fraction of pts with mutNPM1 were MRD– (61.7%) than were MRD+ (38.4%) at screening (P=0.0178). For pts with WT NPM1 (Oral-AZA n=170; PBO n=162), Tx with Oral-AZA significantly increased OS (19.6 vs 14.6 mo; HR 0.77; P=0.0365) and RFS (7.7 vs 4.6 mo; HR 0.69; P=0.0029). Pts with WT NPM1 were evenly distributed between MRD– (49.2%) and MRD+ (50.8%) status at screening.

Conclusion
Oral-AZA considerably improved survival for pts with de novo AML and int-risk cytogenetics. Additionally, pts with mutNPM1 in the Oral-AZA arm derived an extended OS benefit of more than 2.5 years vs PBO, whereas OS for all pts in QUAZAR AML-001 was lengthened by 9.9 months with Oral-AZA vs PBO. This suggests that mutNPM1 status is both prognostically favorable in general and independently predictive of increased OS with Oral-AZA.

Keyword(s): AML, Azacitidine, Maintenance, Mutation

Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S131

Type: Oral Presentation

Session title: AML classification

Background
Oral azacitidine (Oral-AZA; CC-486) is approved in the US for adult patients (pts) with acute myeloid leukemia (AML) who have achieved first complete remission (CR) or CR with incomplete blood count recovery (CRi) after intensive chemotherapy and are ineligible for intensive curative therapy. In the phase 3 QUAZAR trial, Oral-AZA significantly improved overall survival (OS) vs placebo (PBO) (median [med] 24.7 vs 14.8 months [mo], respectively; P<0.001). It has not been elucidated which subgroups of pts may derive greater benefit from Oral-AZA maintenance treatment (Tx) based on prognostic features or mutational profile.

Aims
Investigate the relationship between Oral-AZA and survival in post hoc analyses based on cytogenetic risk classification, AML subtype (de novo or secondary), and NPM1/FLT3 status at diagnosis (Dx).

Methods
Cytogenetic risk classification of intermediate- (int) and poor-risk pts was based on the 2012 NCCN Guidelines; pts with favorable risk were excluded. Pts were randomized 1:1 to Oral-AZA 300 mg or PBO within 4 mo of achieving first CR/CRi. Mutant (mut) or wild-type (WT) NPM1/FLT3-ITD status was determined at Dx. OS and relapse-free survival (RFS) were estimated using Kaplan-Meier methods. Cox Proportional Hazard Regression was used to obtain hazard ratios (HR; P values, Log-rank test). Measurable residual disease (MRD) analysis used a cutoff of ≥0.1% (P values, Fisher’s exact test).

Results
Of 472 randomized pts, 90.9% had de novo AML, and Oral-AZA provided a significant increase in med OS vs PBO (23.2 vs 14.6 mo; HR 0.73; P=0.0068) and RFS (10.2 vs 4.9 mo; HR 0.66; P=0.0002). For the underpowered pt group with secondary AML (n=43), there was a trend for increased OS with Oral-AZA vs PBO (28.2 vs 15.7 mo; HR 0.58; P=0.11) and significantly increased RFS (4.7 vs 2.4 mo; HR 0.47; P=0.0118). 86% of pts had int-risk cytogenetics, and within this population, OS was significantly increased with Oral-AZA vs PBO (25.4 vs 15.9 mo; HR 0.73; P=0.0093), as was RFS (11.0 vs 5.8 mo; HR 0.66; P=0.0004). The poor-risk cohort (14%; n=66), though underpowered, showed a trend for increased OS with Oral-AZA vs PBO (13.9 vs. 7.4 mo; HR 0.61; P=0.06), and RFS was similar (Oral-AZA 4.6 mo, PBO 3.7 mo; HR 0.63; P=0.08). Overall, 29.2% of pts had mutNPM1 at Dx (137/469), 9.8% (n=48) were FLT3-ITD positive, and 6% (n=30) had co-mutated NPM1/FLT3-ITD. In the PBO arm, mutNPM1 status vs WT was prognostically favorable for RFS (6.9 vs 4.6 mo; HR 0.64; P=0.0083) with a trend in increased OS (15.9 vs 14.6 mo; HR 0.75; P=0.10). Comparing treatment arms, the med OS for pts with mutNPM1 was considerably longer in the Oral-AZA arm vs PBO (46.1 vs 15.9 mo; HR 0.57; P=0.0138), and med RFS was significantly prolonged (23.2 vs 6.9 mo; HR 0.55; P=0.0098) (Figure). A larger fraction of pts with mutNPM1 were MRD– (61.7%) than were MRD+ (38.4%) at screening (P=0.0178). For pts with WT NPM1 (Oral-AZA n=170; PBO n=162), Tx with Oral-AZA significantly increased OS (19.6 vs 14.6 mo; HR 0.77; P=0.0365) and RFS (7.7 vs 4.6 mo; HR 0.69; P=0.0029). Pts with WT NPM1 were evenly distributed between MRD– (49.2%) and MRD+ (50.8%) status at screening.

Conclusion
Oral-AZA considerably improved survival for pts with de novo AML and int-risk cytogenetics. Additionally, pts with mutNPM1 in the Oral-AZA arm derived an extended OS benefit of more than 2.5 years vs PBO, whereas OS for all pts in QUAZAR AML-001 was lengthened by 9.9 months with Oral-AZA vs PBO. This suggests that mutNPM1 status is both prognostically favorable in general and independently predictive of increased OS with Oral-AZA.

Keyword(s): AML, Azacitidine, Maintenance, Mutation

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