PMID- 34972214
OWN - NLM
STAT- MEDLINE
DCOM- 20220405
LR  - 20220608
IS  - 2473-9537 (Electronic)
IS  - 2473-9529 (Print)
IS  - 2473-9529 (Linking)
VI  - 6
IP  - 7
DP  - 2022 Apr 12
TI  - A randomized phase 2 trial of azacitidine with or without durvalumab as 
      first-line therapy for higher-risk myelodysplastic syndromes.
PG  - 2207-2218
LID - 10.1182/bloodadvances.2021005487 [doi]
AB  - Azacitidine-mediated hypomethylation promotes tumor cell immune recognition but 
      may increase the expression of inhibitory immune checkpoint molecules. We 
      conducted the first randomized phase 2 study of azacitidine plus the immune 
      checkpoint inhibitor durvalumab vs azacitidine monotherapy as first-line 
      treatment for higher-risk myelodysplastic syndromes (HR-MDS). In all, 84 patients 
      received 75 mg/m2 subcutaneous azacitidine (days 1-7 every 4 weeks) combined with 
      1500 mg intravenous durvalumab on day 1 every 4 weeks (Arm A) for at least 6 
      cycles or 75 mg/m(2) subcutaneous azacitidine alone (days 1-7 every 4 weeks) for at 
      least 6 cycles (Arm B). After a median follow-up of 15.25 months, 8 patients in 
      Arm A and 6 in Arm B remained on treatment. Patients in Arm A received a median 
      of 7.9 treatment cycles and those in Arm B received a median of 7.0 treatment 
      cycles with 73.7% and 65.9%, respectively, completing >/=4 cycles. The overall 
      response rate (primary end point) was 61.9% in Arm A (26 of 42) and 47.6% in Arm 
      B (20 of 42; P = .18), and median overall survival was 11.6 months (95% 
      confidence interval, 9.5 months to not evaluable) vs 16.7 months (95% confidence 
      interval, 9.8-23.5 months; P = .74). Durvalumab-related adverse events (AEs) were 
      reported by 71.1% of patients; azacitidine-related AEs were reported by 82% (Arm 
      A) and 81% (Arm B). Grade 3 or 4 hematologic AEs were reported in 89.5% (Arm A) 
      vs 68.3% (Arm B) of patients. Patients with TP53 mutations tended to have a worse 
      response than patients without these mutations. Azacitidine increased programmed 
      cell death ligand 1 (PD-L1 [CD274]) surface expression on bone marrow 
      granulocytes and monocytes, but not blasts, in both arms. In summary, combining 
      azacitidine with durvalumab in patients with HR-MDS was feasible but with more 
      toxicities and without significant improvement in clinical outcomes over 
      azacitidine alone. This trial was registered at www.clinicaltrials.gov as 
      #NCT02775903.
CI  - (c) 2022 by The American Society of Hematology. Licensed under Creative Commons 
      Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), 
      permitting only noncommercial, nonderivative use with attribution. All other 
      rights reserved.
FAU - Zeidan, Amer M
AU  - Zeidan AM
AD  - Yale University and Yale Cancer Center, New Haven, CT.
FAU - Boss, Isaac
AU  - Boss I
AD  - Bristol Myers Squibb, Princeton, NJ.
FAU - Beach, C L
AU  - Beach CL
AD  - Bristol Myers Squibb, Princeton, NJ.
FAU - Copeland, Wilbert B
AU  - Copeland WB
AD  - Bristol Myers Squibb, Princeton, NJ.
FAU - Thompson, Ethan
AU  - Thompson E
AD  - Bristol Myers Squibb, Princeton, NJ.
FAU - Fox, Brian A
AU  - Fox BA
AUID- ORCID: 0000-0001-6620-3853
AD  - Bristol Myers Squibb, Princeton, NJ.
FAU - Hasle, Vanessa E
AU  - Hasle VE
AD  - Bristol Myers Squibb, Princeton, NJ.
FAU - Ogasawara, Ken
AU  - Ogasawara K
AUID- ORCID: 0000-0002-4264-8927
AD  - Bristol Myers Squibb, Princeton, NJ.
FAU - Cavenagh, James
AU  - Cavenagh J
AD  - Barts Health National Health Service Trust, St. Bartholomew's Hospital, West 
      Smithfield, London, United Kingdom.
FAU - Silverman, Lewis R
AU  - Silverman LR
AD  - Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY.
FAU - Voso, Maria Teresa
AU  - Voso MT
AUID- ORCID: 0000-0002-6164-4761
AD  - AF Oncoematologia-Universita' di Roma Tor Vergata, Rome, Italy.
FAU - Hellmann, Andrzej
AU  - Hellmann A
AD  - University Clinical Center of Medical University of Gdansk, Gdansk, Poland.
FAU - Tormo, Mar
AU  - Tormo M
AD  - Hospital Clinico Universitario de Valencia and INCLIVA Biomedical Research 
      Institute, Valencia, Spain; and.
FAU - O'Connor, Tim
AU  - O'Connor T
AD  - Bristol Myers Squibb, Princeton, NJ.
FAU - Previtali, Alessandro
AU  - Previtali A
AD  - Bristol Myers Squibb, Princeton, NJ.
FAU - Rose, Shelonitda
AU  - Rose S
AD  - Bristol Myers Squibb, Princeton, NJ.
FAU - Garcia-Manero, Guillermo
AU  - Garcia-Manero G
AD  - MD Anderson Cancer Center, Houston, TX.
LA  - eng
SI  - ClinicalTrials.gov/NCT02775903
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood Adv
JT  - Blood advances
JID - 101698425
RN  - 0 (Antibodies, Monoclonal)
RN  - 28X28X9OKV (durvalumab)
RN  - M801H13NRU (Azacitidine)
SB  - IM
MH  - *Antibodies, Monoclonal/adverse effects
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse effects
MH  - *Azacitidine/adverse effects
MH  - Humans
MH  - *Myelodysplastic Syndromes/drug therapy
PMC - PMC9006291
EDAT- 2022/01/01 06:00
MHDA- 2022/04/06 06:00
PMCR- 2022/04/01
CRDT- 2021/12/31 20:33
PHST- 2021/06/09 00:00 [received]
PHST- 2021/11/29 00:00 [accepted]
PHST- 2022/01/01 06:00 [pubmed]
PHST- 2022/04/06 06:00 [medline]
PHST- 2021/12/31 20:33 [entrez]
PHST- 2022/04/01 00:00 [pmc-release]
AID - 483294 [pii]
AID - 2022/ADV2021005487 [pii]
AID - 10.1182/bloodadvances.2021005487 [doi]
PST - ppublish
SO  - Blood Adv. 2022 Apr 12;6(7):2207-2218. doi: 10.1182/bloodadvances.2021005487.