Delays in Time to Deterioration of Health-Related Quality of Life Were Observed in Patients with Acute Myeloid Leukemia Receiving Venetoclax in Combination with Azacitidine or in Combination with Low-Dose Cytarabine
Authors: Pratz Keith W. , Panayiotidis Panayiotis , Recher Christian , Wei Xudong , Jonas Brian A , Montesinos Pau , Ivanov Vladimir , Schuh Andre C. , Dinardo Courtney D. , Novak Jan , Pejsa Vlatko , Stevens Don A. , Yeh Su-Peng , Kim Inho , Turgut Mehmet , Fracchiolla Nicola , Yamamoto Kazuhito , Ofran Yishai , Wei Andrew H , Bui Cat , Benjamin Katy , Kamalakar Rajesh , Potluri Jalaja , Mendes Wellington , Devine Jacob , Fiedler Walter 
Published: February 2021

Background : For patients (pts) with acute myeloid leukemia (AML), preserving and measuring perceptions of health-related quality of life (HRQoL) is important, particularly for those ineligible for intensive chemotherapy and with a poor prognosis, especially when evaluating new treatment regimens. This analysis from 2 Phase 3 trials, Viale-A (NCT02993523) and Viale-C (NCT03069352), evaluated HRQoL, including key symptoms and aspects of functioning, in pts with AML receiving venetoclax (VEN) co-administered with azacitidine (AZA) (Viale-A) or low-dose cytarabine (LDAC) (Viale-C).
Methods: Viale-A and Viale-C included treatment-naïve pts with AML, ≥18 years of age, and ineligible to receive intensive chemotherapy. Pts were randomized 2:1 to receive VEN +AZA or placebo (PBO)+AZA in Viale-A, and VEN+ LDAC or PBO+LDAC in Viale-C. Pt-reported outcome (PRO) measures included the PROMIS Cancer Fatigue Short Form 7a, the EORTC QLQ-C30 global health status (GHS)/QoL and physical functioning [PF] subscales, and the EQ-5D-5L health status visual analog scale (VAS). PRO data were collected on Day 1 of every 28-day cycle throughout both trials. Time to deterioration (TTD) was assessed to quantify differences between treatment groups. TTD was defined as worsening from baseline in PRO-specific meaningful change thresholds of ≥10, 7, or 5 points for the EORTC-QLQ-C30, EQ-5D-5L VAS, and PROMIS Fatigue, respectively. TTD differences between treatment arms were analyzed using Kaplan-Meier curves, unadjusted log-rank tests, and Cox PH models adjusted for key covariates (age, baseline ECOG and PRO scores, AML type, and cytogenetic risk category). TTD analyses were conducted for all pts in the full dataset who survived up to a given assessment with available data on ≥1 PRO measures from baseline.
Results: Viale-A included 431 pts (VEN+AZA: 286, PBO+AZA: 145), of whom 60% were male; median age was 76 years. Compared with PBO+AZA pts, VEN+AZA pts had a non-statistically significant trend to longer TTD in GHS/QoL (median in months [95% CI]: 16.5 [95% CI: 9.8, NE] vs. 9.3 [95% CI: 4.7, 16.6], P=0.066) and fatigue (9.3 [7.2, 16.6] vs. 8.6 [4.2, 16.6], P=0.189) (Figure 1A, B). VEN+AZA pts had significantly longer TTD in PF (9.7 [6.7, 16.0] vs. 6.2 [4.7, 9.5], P=0.028) and health status VAS (10.7 [7.5, 18.6] vs. 3.9 [2.4, 7.4], P&lt;0.001) than did PBO+AZA pts (Figure 1C, D). Viale-C included 211 pts (VEN+LDAC: 143, PBO+LDAC: 68), of whom 55% were male; median age was 76 years. Compared with PBO+LDAC, VEN+LDAC pts had significantly longer TTD in GHS/QoL (11.3 [4.2, NE] vs. 2.6 [2.0, 9.3], P=0.011), fatigue (8.1 [5.8, NE] vs. 2.6 [2.1, 9.5], P=0.004), and PF (5.8 [3.1, NE] vs. 2.9 [2.0, 8.1], P=0.020), and a trend in health status VAS (4.9 [2.8, NE] vs. 2.5 [2.0, 9.5], P=0.057) (Figure 2A-D). Cox PH models demonstrated consistently longer TTD in all PRO measures for the VEN arms compared with PBO in both trials, with significant differences for all measures in Viale-C, and for PF and health status VAS in Viale-A (P≤0.01) (Table 1).
Conclusions: Results showed a longer TTD in PRO measures of global health status, VAS, fatigue, and PF for pts receiving VEN combinations vs AZA or LDAC monotherapy, with significantly longer TTD observed for all PRO measures from the unadjusted and adjusted analyses in Viale-C, and for PF and health VAS in Viale-A. These results suggest that VEN conveys meaningful benefit in terms of HRQoL. Limitations included the small sample size beyond early cycles in these studies; however, the early separation of the TTD curves with the initial larger sample size, suggests that these results are not due to chance variability and are statistically valid. Overall the improvements in PROs with VEN are consistent with previous efficacy reports. In summary, VEN appears to have a positive impact on the HRQoL of pts with AML who are ineligible for intensive chemotherapy, leading to a longer preservation of functioning and overall health status.

Disclosures
Pratz: Millennium: Research Funding; Daiichi Sankyo: Research Funding; Agios: Other: Scientific Advisory Board, Research Funding; Celgene: Other: Scientific Advisory Board; Boston BioMedical: Consultancy; AbbVie: Other: Scientific Advisory Board, Research Funding; Astellas: Other: Scientific Advisory Board, Research Funding; Jazz Pharmaceutical: Consultancy. Panayiotidis:AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Genesis: Honoraria, Research Funding; Takeda: Honoraria; Phizer: Honoraria; ASH: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Jonas:AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Tolero: Consultancy; Treadwell: Consultancy; Forty Seven: Research Funding; Daiichi Sankyo: Research Funding; Genentech/Roche: Research Funding; Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GlycoMimetics: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Accelerated Medical Diagnostics: Research Funding; AROG: Research Funding; LP Therapeutics: Research Funding; Forma: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Jazz: Consultancy, Research Funding; Sigma Tau: Research Funding; Celgene: Consultancy, Research Funding; F. Hoffmann-La Roche: Research Funding; Incyte: Research Funding; Hanmi: Research Funding; Takeda: Consultancy. Dinardo:Takeda: Honoraria; Celgene: Research Funding; Agios: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Calithera: Research Funding; ImmuneOnc: Honoraria. Novak:Janssen: Other: Travel expenses; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Other: Travel expenses; Takeda: Consultancy. Pejsa:Oktal Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alvogen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pliva: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stevens:Amgen, MorphoSys: Consultancy. Yeh:Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees. Kim:AbbVie: Other: Clinical trials investigator. Fracchiolla:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Yamamoto:Takeda: Consultancy, Honoraria, Research Funding; Yakult: Research Funding; Zenyaku: Research Funding; SymBio: Research Funding; Solasia Pharma: Research Funding; Aichi Cancer Center: Current Employment; AbbVie: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Bayer: Research Funding; Bristol-Myers Squibb: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy; IQIVA/HUYA: Honoraria; HUYA: Consultancy; IQIVA/Incyte: Research Funding; Gilead Sciences: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria; Mochida: Honoraria; MSD: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Sanofi: Honoraria; Sumitomo Dainippon: Honoraria; Stemline Therapeutics: Consultancy. Ofran:AbbVie: Membership on an entity's Board of Directors or advisory committees. Wei:Astra Zeneca: Honoraria, Research Funding; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: AW is eligible for royalty payments related to venetoclax; Novartis: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; Macrogenics: Honoraria; Roche: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Janssen: Honoraria; Abbvie: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau. Bui:AbbVie: Current Employment, Current equity holder in publicly-traded company. Benjamin:AbbVie: Current Employment, Current equity holder in publicly-traded company. Kamalakar:AbbVie: Current Employment, Other: may hold stock or other options. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Mendes:AbbVie: Current Employment, Current equity holder in publicly-traded company. Devine:Genentech: Current Employment, Current equity holder in publicly-traded company. Fiedler:Daiichi Sankyo: Other: support for meeting attendance; Gilead: Other: support for meeting attendance; Jazz Pharmaceuticals: Honoraria, Other: support for meeting attendance; Abbvie: Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria; ARIAD/Incyte: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: support for meeting attendance, Patents & Royalties, Research Funding.