A PHASE III PLACEBO-CONTROLLED TRIAL OF CC-486 IN PATIENTS WITH RED BLOOD CELL TRANSFUSION-DEPENDENT (RBC-TD) ANEMIA AND THROMBOCYTOPENIA DUE TO IPSS LOWER-RISK MYELODYSPLASTIC SYNDROMES (LR-MDS)
Author(s): ,
Guillermo Garcia-Manero
Affiliations:
University of Texas MD Anderson Cancer Center,Houston,United States
,
Valeria Santini
Affiliations:
MDS Unit, Hematology, University of Florence,Florence,Italy
,
Antonio Almeida
Affiliations:
Hospital da Luz Lisboa,Lisbon,Portugal
,
Uwe Platzbecker
Affiliations:
Universitätsklinikum Leipzig,Leipzig,Germany
,
Anna Jonasova
Affiliations:
Charles University and General University Hospital,Prague,Czech Republic
,
Lewis Silverman
Affiliations:
Icahn School of Medicine at Mount Sinai,New York,United States
,
Jose Falantes
Affiliations:
Hospital Universitario Virgen del Rocio,Seville,Spain
,
Gianluigi Reda
Affiliations:
Fondazione IRCCS Ca Granda, Ospedale Maggiore Policlinico,Milan,Italy
,
Francesco Buccisano
Affiliations:
Fondazione PTV Policlinico Tor Vergata,Rome,Italy
,
Pierre Fenaux
Affiliations:
Hôpital St Louis, Université Paris,Paris,France
,
Rena Buckstein
Affiliations:
Sunnybrook Health Sciences Centre,Toronto,Canada
,
María Díez Campelo
Affiliations:
Hospital Universitario de Salamanca,Salamanca,Spain
,
Stephen Larsen
Affiliations:
Royal Prince Alfred Hospital,Sydney,Australia
,
David Valcarcel
Affiliations:
Hospital Universitari Vall d'Hebron,Barcelona,Spain
,
Paresh Vyas
Affiliations:
MRC Molecular Haematology Unit and Oxford Biomedical Research Centre, University of Oxford and Oxford University Hospitals,Oxford,United Kingdom
,
Valentina Giai
Affiliations:
Antonio e Biagio e Cesare Arrigo Hospital,Alessandria,Italy
,
Esther Natalie Olíva
Affiliations:
Grande Ospedale Metropolitano Bianchi Melacrino Morelli,Reggio Calabria,Italy
,
Jake Shortt
Affiliations:
Monash University and Monash Health,Melbourne,Australia
,
Dietger Niederwieser
Affiliations:
University of Leipzig,Leipzig,Germany
,
Moshe Mittelman
Affiliations:
Tel Aviv Sourasky Medical Center,Tel Aviv,Israel
,
Luana Fianchi
Affiliations:
Fondazione Policlinico Universitario A. Gemelli, IRCCS,Rome,Italy
,
Jim Zhong
Affiliations:
Bristol-Myers Squibb,Summit,United States
,
Eric Laille
Affiliations:
Bristol-Myers Squibb,Summit,United States
,
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
,
CL Beach
Affiliations:
Bristol-Myers Squibb,Summit,United States
Aristoteles Giagounidis
Affiliations:
Marien Hospital Düsseldorf,Düsseldorf,Germany
EHA Library. Garcia-Manero G. 06/12/20; 295000; S180
Dr. Guillermo Garcia-Manero
Dr. Guillermo Garcia-Manero
Contributions
Abstract

Abstract: S180

Type: Oral Presentation

Presentation during EHA25: All oral abstract 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.

Session title: Novel treatments for MDS I

Background
MDS is characterized by bone marrow dysplasia and peripheral cytopenias of variable severity. Treatment (Tx) options are limited for LR-MDS patients (pts) with low blast counts but high-risk disease features (eg, RBC-TD anemia and thrombocytopenia). The phase III placebo (PBO)-controlled QUAZAR Lower-risk MDS trial (NCT01566695) assessed CC-486, an oral hypomethylating agent, in pts who were RBC-TD and thrombocytopenic at study entry.

Aims
Describe clinical outcomes from the QUAZAR Lower-risk MDS trial.

Methods
Eligible pts were age ≥18 yrs, with IPSS LR-MDS, average RBC transfusion requirement of ≥2 units (U)/28 days (d) for 56d, and 2 platelet (PLT) counts ≤75 × 109/L taken ≥21d apart. Pts were randomized 1:1 to CC-486 300mg or PBO QD for 21d per 28d Tx cycle (C). The primary endpoint was RBC transfusion independence (TI) lasting ≥56d (IWG 2006). Key secondary endpoints were overall survival (OS), ≥84d RBC-TI, and hematologic improvement in erythroid and PLT lineages (HI-E, HI-P). Planned enrollment was 386 pts. An imbalance of early deaths in the CC-486 arm led to a decision to close enrollment; the final sample size (N=216) allowed comparison of RBC-TI between Tx arms with ~99% power.

Results
At data cutoff all pts (CC-486 n=107; PBO n=109) completed ≥12 mo of Tx or discontinued before 12 mo. Baseline (BL) characteristics were similar between Tx arms. Median age was 74 yrs (30–89), Hgb 8.1 g/dL (5.4–10.9), PLT count 25×109/L (5–73), ANC 1.3×109/L (0.1–25), and transfusion requirement 6.7 U/56d. All pts had IPSS INT-1 MDS.

Significantly more pts in the CC-486 arm achieved RBC-TI for ≥56d (31%, vs. 11% with PBO; P=0.0002) (Table 1). Median RBC-TI  durations in the CC-486 and PBO arms were 11.1 and 5.0 mo, respectively (P=0.42). In the CC-486 and PBO arms, 42% and 31%, respectively, had RBC transfusion reductions of ≥4 U from BL, sustained for a median of 10.0 and 2.3 mo (P=0.0001). While HI-E rates were comparable (P=0.12), significantly more CC-486 pts had a ≥1.5 g/dL Hgb increase from BL (P<0.0001). HI-P rate was significantly higher in the CC-486 arm (P=0.0003). PLT-TI (≥56d) rates were similar between arms, but median PLT-TI duration was longer with CC-486 (12.1 vs. 4.4 mo with PBO). In the CC-486 arm, mean Hgb increased by ~2 g/dL from BL by C6, and PLT count increased by 38×109/L by C3. Hgb and PLT improvements were sustained during Tx. Hgb and PLT count changes were negligible with PBO.

Study sample size was underpowered for interim OS analysis, which showed no difference between CC-486 and PBO (median 17.3 vs. 16.7 mo; P=0.88).

Median Tx durations were 5 CC-486 cycles (1–70) and 6 PBO cycles (1–69). Most common AEs in both Tx arms were grade 1-2 GI events. In the CC-486 and PBO arms, respectively, 90% and 73% of pts had a grade 3-4 AE (Table 2), and 30% and 28% discontinued Tx due to any AE. Tx-related AEs were more common with CC-486, most occurring during C1–C2. Overall death rate was similar between Tx arms but there was an imbalance in early (d1–56) deaths (CC-486 n=16, PBO n=6), most related to infection; those CC-486 pts had a median BL ANC of ~0.5×109/L.

Conclusion
These IPSS INT-1 LR-MDS pts have unfavorable disease features, including RBC-TD and thrombocytopenia, and poor prognosis, indicating a need for disease-modifying Tx. CC-486 met the primary endpoint of RBC-TI and induced durable bilineage Hgb and PLT improvements. AEs were more frequent with CC-486. Pts with severe neutropenia pre-Tx are at higher risk for hematologic toxicity during early CC-486 Tx and may benefit from a modified dosing regimen.

Session topic: 10. Myelodysplastic syndromes - Clinical

Keyword(s): Azacitidine, Hemoglobin, MDS, Transfusion

Abstract: S180

Type: Oral Presentation

Presentation during EHA25: All oral abstract 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.

Session title: Novel treatments for MDS I

Background
MDS is characterized by bone marrow dysplasia and peripheral cytopenias of variable severity. Treatment (Tx) options are limited for LR-MDS patients (pts) with low blast counts but high-risk disease features (eg, RBC-TD anemia and thrombocytopenia). The phase III placebo (PBO)-controlled QUAZAR Lower-risk MDS trial (NCT01566695) assessed CC-486, an oral hypomethylating agent, in pts who were RBC-TD and thrombocytopenic at study entry.

Aims
Describe clinical outcomes from the QUAZAR Lower-risk MDS trial.

Methods
Eligible pts were age ≥18 yrs, with IPSS LR-MDS, average RBC transfusion requirement of ≥2 units (U)/28 days (d) for 56d, and 2 platelet (PLT) counts ≤75 × 109/L taken ≥21d apart. Pts were randomized 1:1 to CC-486 300mg or PBO QD for 21d per 28d Tx cycle (C). The primary endpoint was RBC transfusion independence (TI) lasting ≥56d (IWG 2006). Key secondary endpoints were overall survival (OS), ≥84d RBC-TI, and hematologic improvement in erythroid and PLT lineages (HI-E, HI-P). Planned enrollment was 386 pts. An imbalance of early deaths in the CC-486 arm led to a decision to close enrollment; the final sample size (N=216) allowed comparison of RBC-TI between Tx arms with ~99% power.

Results
At data cutoff all pts (CC-486 n=107; PBO n=109) completed ≥12 mo of Tx or discontinued before 12 mo. Baseline (BL) characteristics were similar between Tx arms. Median age was 74 yrs (30–89), Hgb 8.1 g/dL (5.4–10.9), PLT count 25×109/L (5–73), ANC 1.3×109/L (0.1–25), and transfusion requirement 6.7 U/56d. All pts had IPSS INT-1 MDS.

Significantly more pts in the CC-486 arm achieved RBC-TI for ≥56d (31%, vs. 11% with PBO; P=0.0002) (Table 1). Median RBC-TI  durations in the CC-486 and PBO arms were 11.1 and 5.0 mo, respectively (P=0.42). In the CC-486 and PBO arms, 42% and 31%, respectively, had RBC transfusion reductions of ≥4 U from BL, sustained for a median of 10.0 and 2.3 mo (P=0.0001). While HI-E rates were comparable (P=0.12), significantly more CC-486 pts had a ≥1.5 g/dL Hgb increase from BL (P<0.0001). HI-P rate was significantly higher in the CC-486 arm (P=0.0003). PLT-TI (≥56d) rates were similar between arms, but median PLT-TI duration was longer with CC-486 (12.1 vs. 4.4 mo with PBO). In the CC-486 arm, mean Hgb increased by ~2 g/dL from BL by C6, and PLT count increased by 38×109/L by C3. Hgb and PLT improvements were sustained during Tx. Hgb and PLT count changes were negligible with PBO.

Study sample size was underpowered for interim OS analysis, which showed no difference between CC-486 and PBO (median 17.3 vs. 16.7 mo; P=0.88).

Median Tx durations were 5 CC-486 cycles (1–70) and 6 PBO cycles (1–69). Most common AEs in both Tx arms were grade 1-2 GI events. In the CC-486 and PBO arms, respectively, 90% and 73% of pts had a grade 3-4 AE (Table 2), and 30% and 28% discontinued Tx due to any AE. Tx-related AEs were more common with CC-486, most occurring during C1–C2. Overall death rate was similar between Tx arms but there was an imbalance in early (d1–56) deaths (CC-486 n=16, PBO n=6), most related to infection; those CC-486 pts had a median BL ANC of ~0.5×109/L.

Conclusion
These IPSS INT-1 LR-MDS pts have unfavorable disease features, including RBC-TD and thrombocytopenia, and poor prognosis, indicating a need for disease-modifying Tx. CC-486 met the primary endpoint of RBC-TI and induced durable bilineage Hgb and PLT improvements. AEs were more frequent with CC-486. Pts with severe neutropenia pre-Tx are at higher risk for hematologic toxicity during early CC-486 Tx and may benefit from a modified dosing regimen.

Session topic: 10. Myelodysplastic syndromes - Clinical

Keyword(s): Azacitidine, Hemoglobin, MDS, Transfusion

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