ESCALATED DOSING SCHEDULES OF CC-486 ARE EFFECTIVE AND WELL TOLERATED FOR PATIENTS EXPERIENCING FIRST ACUTE MYELOID LEUKEMIA (AML) RELAPSE: RESULTS FROM THE PHASE III QUAZAR AML-001 MAINTENANCE TRIAL
Author(s): ,
Hartmut Döhner
Affiliations:
Ulm University Hospital,Ulm,Germany
,
Andrew Wei
Affiliations:
The Alfred Hospital and Monash University,Melbourne,Australia
,
Pau Montesinos
Affiliations:
Hospital Universitario y Politécnico La Fe,Valencia,Spain;CIBERONC, Instituto Carlos III,Madrid,Spain
,
Hervé Dombret
Affiliations:
Hôpital Saint-Louis, Assistance Publique – Hôpitaux de Paris (AP-HP) and Institut de Recherche Saint-Louis, Université de Paris,Paris,France
,
Farhad Ravandi
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston,United States
,
Hamid Sayar
Affiliations:
Indiana University Cancer Center,Indianapolis,United States
,
Kimmo Porkka
Affiliations:
Helsinki University Hospital Comprehensive Cancer Center,Helsinki,Finland
,
Irwindeep Sandhu
Affiliations:
University of Alberta Hospital,Edmonton,Canada
,
Francesco Passamonti
Affiliations:
University of Insubria,Varese,Italy
,
Fabrizio Pane
Affiliations:
Azienda Ospedaliera Universitaria Federico II,Napes,Italy
,
Tadeusz Robak
Affiliations:
Medical University of Lodz, Copernicus Memorial Hospital,Lodz,Poland
,
Jose Falantes
Affiliations:
Hospital Virgen del Rocio,Seville,Spain
,
Andre Schuh
Affiliations:
Princess Margaret Cancer Centre,Toronto,Canada
,
Gert Ossenkoppele
Affiliations:
Amsterdam UMC, Location VUMC,Amsterdam,Netherlands
,
Ignazia La Torre
Affiliations:
Bristol-Myers Squibb,Summit,United States
,
Barry Skikne
Affiliations:
Bristol-Myers Squibb,Summit,United States;University of Kansas Medical Center,Kansas City,United States
,
Keshava Kumar
Affiliations:
Bristol-Myers Squibb,Summit,United States
,
Qian Dong
Affiliations:
Bristol-Myers Squibb,Summit,United States
,
CL Beach
Affiliations:
Bristol-Myers Squibb,Summit,United States
Gail Roboz
Affiliations:
Weill Cornell Medical College,New York,United States;New York Presbyterian Hospital,New York,United States
EHA Library. Döhner H. 06/12/20; 294479; EP561
Prof. Dr. Hartmut Döhner
Prof. Dr. Hartmut Döhner
Contributions
Abstract

Abstract: EP561

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background
Standard treatment (Tx) with intensive induction chemotherapy (IC) for AML induces complete remission (CR) in 60%–80% of patients (pts) aged ≤60 years and in 40%–60% of pts aged >60 years. However, about two-thirds of pts relapse after frontline therapy and most relapses occur within the first 18 months (Yilmaz, Blood Cancer J, 2019). Effective AML maintenance Tx should decrease the risk of relapse by suppressing growth of post-induction residual leukemic cells. CC-486 is an oral hypomethylating agent that allows for extended dosing schedules (>7 days [d]/28d cycle) to sustain therapeutic activity. In the phase III international, randomized, double-blind QUAZAR AML-001 trial (NCT01757535), CC-486 significantly prolonged overall survival (OS) and relapse-free survival vs. placebo (PBO) in pts with AML in first remission following IC, who were not candidates for hematopoietic stem cell transplant (HSCT). Pts initially received CC-486 or PBO for 14d/28d cycle, but pts identified to have early AML relapse with 5–15% blasts in peripheral blood or bone marrow could receive an escalated 21d/cycle dosing schedule.

Aims
To evaluate clinical outcomes in pts in QUAZAR AML-001 who developed 5–15% blasts on-study and then received escalated 21d/cycle dosing of study drug.

Methods
Pts were aged ≥55 years, had intermediate- or poor-risk cytogenetics and ECOG PS scores ≤3, and achieved a first CR or CR with incomplete hematologic recovery (CRi) after IC ± consolidation. Within 4 months of achieving CR/CRi, pts were randomized 1:1 to receive once-daily CC-486 300 mg or PBO on d 1–14 of 28d Tx cycles. CR/CRi status was assessed centrally every 3 cycles. Pts who developed 5%–15% blasts in blood or bone marrow could receive study drug for 21d/cycle at the investigator’s discretion. Tx could continue until >15% blasts, unacceptable toxicity, or HSCT. 

Results
91 patients (CC-486, 51/238 [21%]; PBO, 40/234 [17%]) were identified as having early AML relapse with 5–15% blasts and were assigned to receive 1 or more 21d/cycle dosing schedule. Median time to dose escalation of CC-486 was 9.2 months (range 1.0–52.7) and of PBO was 6.0 months (0.5–19.3). Median number of 21d dosing cycles was 2.0 in both the CC-486 (range 1–45) and PBO (1–16) arms, but proportionally more pts in the CC-486 arm received >3 cycles of 21d dosing (CC-486 43%, PBO 18%). Among 78 evaluable pts (ie, their most recent bone marrow on or before d1 of 21d dosing had ≥5% blasts), 10/43 (23%) in the CC-486 arm and 4/35 (11%) in the PBO arm regained CR/CRi (central review) during dose escalation. Median OS from time of randomization was 22.8 months vs. 14.6 months with CC-486 vs. PBO, respectively (HR 0.66 [95%CI 0.42, 1.0]; P=0.073), and 1-year survival rates were 80.4% vs. 59.5% (+20.9% [2.1, 39.7]).

The most common adverse events first reported during 21d dosing were febrile neutropenia (CC-486 24%, PBO 3%), thrombocytopenia (22%, 23%), anemia (22%, 20%), and neutropenia (20%, 10%) (Table). Dose-escalation did not lead to detrimental effects on pt-reported quality of life measures (FACIT-Fatigue and EQ-5D-3L) vs. PBO.

Conclusion
Escalated 21d CC-486 dosing was well tolerated and resulted in restoration of remission in approximately one-fourth of pts. Hematologic AEs first reported during escalated dosing in both Tx arms may be due in part to disease relapse. A 21d dosing schedule should be considered for pts receiving CC-486 who experience relapse with ≤15% blasts.

Session topic: 04. Acute myeloid leukemia - Clinical

Keyword(s): Acute myeloid leukemia, Azacitidine, Elderly, Maintenance

Abstract: EP561

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background
Standard treatment (Tx) with intensive induction chemotherapy (IC) for AML induces complete remission (CR) in 60%–80% of patients (pts) aged ≤60 years and in 40%–60% of pts aged >60 years. However, about two-thirds of pts relapse after frontline therapy and most relapses occur within the first 18 months (Yilmaz, Blood Cancer J, 2019). Effective AML maintenance Tx should decrease the risk of relapse by suppressing growth of post-induction residual leukemic cells. CC-486 is an oral hypomethylating agent that allows for extended dosing schedules (>7 days [d]/28d cycle) to sustain therapeutic activity. In the phase III international, randomized, double-blind QUAZAR AML-001 trial (NCT01757535), CC-486 significantly prolonged overall survival (OS) and relapse-free survival vs. placebo (PBO) in pts with AML in first remission following IC, who were not candidates for hematopoietic stem cell transplant (HSCT). Pts initially received CC-486 or PBO for 14d/28d cycle, but pts identified to have early AML relapse with 5–15% blasts in peripheral blood or bone marrow could receive an escalated 21d/cycle dosing schedule.

Aims
To evaluate clinical outcomes in pts in QUAZAR AML-001 who developed 5–15% blasts on-study and then received escalated 21d/cycle dosing of study drug.

Methods
Pts were aged ≥55 years, had intermediate- or poor-risk cytogenetics and ECOG PS scores ≤3, and achieved a first CR or CR with incomplete hematologic recovery (CRi) after IC ± consolidation. Within 4 months of achieving CR/CRi, pts were randomized 1:1 to receive once-daily CC-486 300 mg or PBO on d 1–14 of 28d Tx cycles. CR/CRi status was assessed centrally every 3 cycles. Pts who developed 5%–15% blasts in blood or bone marrow could receive study drug for 21d/cycle at the investigator’s discretion. Tx could continue until >15% blasts, unacceptable toxicity, or HSCT. 

Results
91 patients (CC-486, 51/238 [21%]; PBO, 40/234 [17%]) were identified as having early AML relapse with 5–15% blasts and were assigned to receive 1 or more 21d/cycle dosing schedule. Median time to dose escalation of CC-486 was 9.2 months (range 1.0–52.7) and of PBO was 6.0 months (0.5–19.3). Median number of 21d dosing cycles was 2.0 in both the CC-486 (range 1–45) and PBO (1–16) arms, but proportionally more pts in the CC-486 arm received >3 cycles of 21d dosing (CC-486 43%, PBO 18%). Among 78 evaluable pts (ie, their most recent bone marrow on or before d1 of 21d dosing had ≥5% blasts), 10/43 (23%) in the CC-486 arm and 4/35 (11%) in the PBO arm regained CR/CRi (central review) during dose escalation. Median OS from time of randomization was 22.8 months vs. 14.6 months with CC-486 vs. PBO, respectively (HR 0.66 [95%CI 0.42, 1.0]; P=0.073), and 1-year survival rates were 80.4% vs. 59.5% (+20.9% [2.1, 39.7]).

The most common adverse events first reported during 21d dosing were febrile neutropenia (CC-486 24%, PBO 3%), thrombocytopenia (22%, 23%), anemia (22%, 20%), and neutropenia (20%, 10%) (Table). Dose-escalation did not lead to detrimental effects on pt-reported quality of life measures (FACIT-Fatigue and EQ-5D-3L) vs. PBO.

Conclusion
Escalated 21d CC-486 dosing was well tolerated and resulted in restoration of remission in approximately one-fourth of pts. Hematologic AEs first reported during escalated dosing in both Tx arms may be due in part to disease relapse. A 21d dosing schedule should be considered for pts receiving CC-486 who experience relapse with ≤15% blasts.

Session topic: 04. Acute myeloid leukemia - Clinical

Keyword(s): Acute myeloid leukemia, Azacitidine, Elderly, Maintenance

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