ASSESSMENT OF DOSE-DEPENDENT RESPONSE TO LUSPATERCEPT IN PATIENTS (PTS) WITH LOWER-RISK MYELODYSPLASTIC SYNDROMES (LR-MDS) WITH RING SIDEROBLASTS IN THE PHASE 3 MEDALIST TRIAL
Author(s): ,
Uwe Platzbecker
Affiliations:
Medical Clinic and Policlinic 1, Hematology and Cellular Therapy,University Hospital Leipzig,Leipzig,Germany
,
Pierre Fenaux
Affiliations:
Service d'Hématologie Séniors,Hôpital Saint-Louis, Université Paris 7,Paris,France
,
Ghulam J. Mufti
Affiliations:
Department of Haemato-Oncology,King's College London,London,United Kingdom
,
Guillermo Garcia-Manero
Affiliations:
Department of Leukemia,University of Texas MD Anderson Cancer Center,Houston, TX,United States
,
Rami S. Komrokji
Affiliations:
Moffitt Cancer Center,Tampa, FL,United States
,
Rena Buckstein
Affiliations:
Odette Cancer Centre,Sunnybrook Health Sciences Centre,Toronto, ON,Canada
,
María Diez-Campelo
Affiliations:
Hematology Department,Institute of Biomedical Research of Salamanca, University Hospital of Salamanca,Salamanca,Spain
,
Carlo Finelli
Affiliations:
Department of Oncology and Hematology,S. Orsola-Malpighi University Hospital,Bologna,Italy
,
Mikkael A. Sekeres
Affiliations:
Department of Hematology and Medical Oncology,Cleveland Clinic,Cleveland, OH,United States
,
Dominik Selleslag
Affiliations:
Department of Haematology,AZ Sint-Jan,Bruges,Belgium
,
Amy E. DeZern
Affiliations:
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins,Baltimore, MD,United States
,
Bruno Quesnel
Affiliations:
Service des Maladies du Sang,Hôpital Huriez, Centre Hospitalier Universitaire de Lille,Lille,France
,
Odile Beyne-Rauzy
Affiliations:
Médicine Interne,Institute Universitaire du Cancer de Toulouse Oncopole,Toulouse,France
,
Maria Teresa Voso
Affiliations:
Dipartimento di Biopatologia e Diagnostica per Immagini,University of Rome Tor Vergata,Rome,Italy
,
Peter L. Greenberg
Affiliations:
Stanford University Cancer Center,Stanford, CA,United States
,
Amer M. Zeidan
Affiliations:
Department of Internal Medicine,Yale School of Medicine and Yale Cancer Center, Yale University,New Haven, CT,United States
,
Lionel Adès
Affiliations:
Service d'Hématologie Séniors,Hôpital Saint-Louis, Université Paris 7,Paris,France
,
Amit Verma
Affiliations:
Department of Oncology,Albert Einstein College of Medicine, Montefiore Medical Center,Bronx, NY,United States
,
Michael R. Savona
Affiliations:
Vanderbilt-Ingram Cancer Center,Vanderbilt University School of Medicine,Nashville, TN,United States
,
Abderrahmane Laadem
Affiliations:
Bristol-Myers Squibb,Summit, NJ,United States
,
Rodrigo Ito
Affiliations:
Bristol-Myers Squibb,Summit, NJ,United States
,
Jennie Zhang
Affiliations:
Bristol-Myers Squibb,Summit, NJ,United States
,
Anita Rampersad
Affiliations:
Bristol-Myers Squibb,Summit, NJ,United States
,
Jessica Morison
Affiliations:
Bristol-Myers Squibb,Summit, NJ,United States
,
Chrystal Louis
Affiliations:
Bristol-Myers Squibb,Summit, NJ,United States
,
Peter G. Linde
Affiliations:
Acceleron Pharma,Cambridge, MA,United States
Valeria Santini
Affiliations:
MDS Unit,Azienda Ospedaliero Universitaria (AOU) Careggi, University of Florence,Florence,Italy
EHA Library. Platzbecker U. 06/12/20; 294729; EP812
Uwe Platzbecker
Uwe Platzbecker
Contributions
Abstract

Abstract: EP812

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
MEDALIST is an ongoing randomized, placebo-controlled, phase 3 study evaluating the efficacy and safety of luspatercept, a first-in-class erythroid maturation agent, for treatment of anemia in pts with LR-MDS (NCT02631070). The primary results of the MEDALIST trial showed a significant proportion of luspatercept-treated pts achieving red blood cell (RBC) transfusion independence (TI) ≥8 weeks (Fenaux P & Platzbecker U, et al. N Engl J Med. 2020;382:140-51).

Aims
To evaluate the effect of luspatercept dose on efficacy and treatment-emergent adverse events (TEAEs). 

Methods
Eligible pts had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS; were ≥18 years old; had unsatisfactory response to or were ineligible for EPO-based therapy; and required regular RBC transfusions. All pts provided written informed consent. 153 pts were randomized to luspatercept; starting dose was 1.0 mg/kg subcutaneously every 3 weeks. Dose titration to 1.33 and 1.75 mg/kg was allowed in the absence of RBC-TI after ≥2 doses at the same dose level (DL). Dose reduction/delay rules were used to manage excessive hemoglobin (Hb) increase and safety.

Results
As of May 8, 2018, 35 (22.9%), 28 (18.3%), and 90 (58.8%) pts received a maximum dose of 1.0, 1.33, and 1.75 mg/kg, respectively. Median time to dose escalation to 1.33 or 1.75 mg/kg in pts achieving RBC-TI ≥8 weeks was approximately twice (105 and 171 days) that of non-responders (43 and 91 days). Dose escalations were more frequently seen in pts with higher EPO levels, intermediate IPSS-R score, and greater RBC transfusion burden at baseline. The majority of patients with baseline transfusion burden ≤6 units/8 weeks achieved RBC-TI ≥8 weeks during Weeks 1–48 (63/108, 58.3%).

Of the 69 luspatercept-treated pts who achieved RBC-TI ≥8 weeks during Weeks 1–48, 47/69 (68.1%) achieved their first response at 1.0 mg/kg, 5/69 (7.2%) at 1.33 mg/kg, and 7/69 (10.1%) at 1.75 mg/kg.

Among 63 luspatercept-treated pts with baseline RBC transfusion burden ≤6 units/8 weeks who achieved RBC-TI ≥8 weeks within the first 48 weeks, 24 (38.1%) received 1.0 mg/kg as maximum DL, 14 (22.2%) received 1.33 mg/kg as maximum DL, and 25 (39.7%) received 1.75 mg/kg as maximum DL. Of these 63 pts, first response occurred at 1.0 mg/kg in 47 (74.6%) pts, at 1.33 mg/kg in 2 (3.2%) pts, and at 1.75 mg/kg in 5 (7.9%) pts; 9 pts received luspatercept at ≥2 DL during their first response period.

As of July 1, 2019, of 153 luspatercept-treated pts, 74 (48.4%) and 9 (5.9%) experienced ≥1 dose delay and ≥1 dose reduction, respectively. Dose delays due to pre-dose Hb levels ≥11.5 g/dL occurred in 13 (8.5%) pts; dose reductions due to Hb increase ≥2 g/dL vs pre-dose Hb of prior treatment cycle occurred in 3 (2.0%) pts. Dose reductions due to any suspected related grade ≥3 adverse event occurred in 5 (3.3%) pts. New onset of TEAEs more frequently reported with luspatercept generally did not increase with dose increases from 1.0 to 1.75 mg/kg (Table).

Conclusion
The majority of pts with baseline transfusion burden ≤6 units/8 weeks who achieved RBC-TI ≥8 weeks within the first 48 weeks achieved their first response at 1.0 mg/kg. An additional 11% of pts in this group (and ~17% of responders overall) achieved their first response only with higher doses (1.33 and 1.75 mg/kg) and dose escalations contributed to maintenance of response or achievement of multiple response episodes. The dose range of 1.0–1.75 mg/kg was well tolerated, without dose-dependent increases in TEAEs.

Session topic: 10. Myelodysplastic syndromes - Clinical

Keyword(s): Clinical trial, MDS, Phase III

Abstract: EP812

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
MEDALIST is an ongoing randomized, placebo-controlled, phase 3 study evaluating the efficacy and safety of luspatercept, a first-in-class erythroid maturation agent, for treatment of anemia in pts with LR-MDS (NCT02631070). The primary results of the MEDALIST trial showed a significant proportion of luspatercept-treated pts achieving red blood cell (RBC) transfusion independence (TI) ≥8 weeks (Fenaux P & Platzbecker U, et al. N Engl J Med. 2020;382:140-51).

Aims
To evaluate the effect of luspatercept dose on efficacy and treatment-emergent adverse events (TEAEs). 

Methods
Eligible pts had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS; were ≥18 years old; had unsatisfactory response to or were ineligible for EPO-based therapy; and required regular RBC transfusions. All pts provided written informed consent. 153 pts were randomized to luspatercept; starting dose was 1.0 mg/kg subcutaneously every 3 weeks. Dose titration to 1.33 and 1.75 mg/kg was allowed in the absence of RBC-TI after ≥2 doses at the same dose level (DL). Dose reduction/delay rules were used to manage excessive hemoglobin (Hb) increase and safety.

Results
As of May 8, 2018, 35 (22.9%), 28 (18.3%), and 90 (58.8%) pts received a maximum dose of 1.0, 1.33, and 1.75 mg/kg, respectively. Median time to dose escalation to 1.33 or 1.75 mg/kg in pts achieving RBC-TI ≥8 weeks was approximately twice (105 and 171 days) that of non-responders (43 and 91 days). Dose escalations were more frequently seen in pts with higher EPO levels, intermediate IPSS-R score, and greater RBC transfusion burden at baseline. The majority of patients with baseline transfusion burden ≤6 units/8 weeks achieved RBC-TI ≥8 weeks during Weeks 1–48 (63/108, 58.3%).

Of the 69 luspatercept-treated pts who achieved RBC-TI ≥8 weeks during Weeks 1–48, 47/69 (68.1%) achieved their first response at 1.0 mg/kg, 5/69 (7.2%) at 1.33 mg/kg, and 7/69 (10.1%) at 1.75 mg/kg.

Among 63 luspatercept-treated pts with baseline RBC transfusion burden ≤6 units/8 weeks who achieved RBC-TI ≥8 weeks within the first 48 weeks, 24 (38.1%) received 1.0 mg/kg as maximum DL, 14 (22.2%) received 1.33 mg/kg as maximum DL, and 25 (39.7%) received 1.75 mg/kg as maximum DL. Of these 63 pts, first response occurred at 1.0 mg/kg in 47 (74.6%) pts, at 1.33 mg/kg in 2 (3.2%) pts, and at 1.75 mg/kg in 5 (7.9%) pts; 9 pts received luspatercept at ≥2 DL during their first response period.

As of July 1, 2019, of 153 luspatercept-treated pts, 74 (48.4%) and 9 (5.9%) experienced ≥1 dose delay and ≥1 dose reduction, respectively. Dose delays due to pre-dose Hb levels ≥11.5 g/dL occurred in 13 (8.5%) pts; dose reductions due to Hb increase ≥2 g/dL vs pre-dose Hb of prior treatment cycle occurred in 3 (2.0%) pts. Dose reductions due to any suspected related grade ≥3 adverse event occurred in 5 (3.3%) pts. New onset of TEAEs more frequently reported with luspatercept generally did not increase with dose increases from 1.0 to 1.75 mg/kg (Table).

Conclusion
The majority of pts with baseline transfusion burden ≤6 units/8 weeks who achieved RBC-TI ≥8 weeks within the first 48 weeks achieved their first response at 1.0 mg/kg. An additional 11% of pts in this group (and ~17% of responders overall) achieved their first response only with higher doses (1.33 and 1.75 mg/kg) and dose escalations contributed to maintenance of response or achievement of multiple response episodes. The dose range of 1.0–1.75 mg/kg was well tolerated, without dose-dependent increases in TEAEs.

Session topic: 10. Myelodysplastic syndromes - Clinical

Keyword(s): Clinical trial, MDS, Phase III

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