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REBLOZYL was studied in the multicenter, randomized, double-blind, placebo-controlled, phase 3 MEDALIST trial1,2


REBLOZYL was studied in the multicenter, randomized, double-blind, placebo-controlled, phase 3 MEDALIST trial.
REBLOZYL was studied in the multicenter,
randomized, double-blind, placebo-controlled, phase 3 MEDALIST trial.

*The primary efficacy assessment was conducted after completion of 24 weeks on study drug. Patients with a decrease in transfusion requirement or increase in Hgb could continue on blinded study drug thereafter until unacceptable toxicity, loss of efficacy, or disease progression.1

del 5q, deletion 5q; EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; SC, subcutaneous.

Primary endpoint1

  • RBC transfusion independence (RBC-TI), defined as the absence of any RBC transfusion during any consecutive 8-week period occurring entirely within the first 24 weeks of treatment

KEY SECONDARY ENDPOINT1

  • RBC-TI for ≥12 weeks during weeks 1 to 24 and 1 to 48

ADDITIONAL SECONDARY ENDPOINTS2

  • RBC-TI for ≥8 weeks at 48 weeks, to capture potential late responders
  • Modified hematologic improvement-erythroid (mHI-E) defined by the International Working Group (IWG) for any consecutive 56-day period
    • Reduction in RBC transfusion burden ≥4 RBC units/8 weeks
    • Mean Hgb increase of ≥1.5 g/dL/8 weeks
  • Duration of response
  • Hgb change from baseline

The MEDALIST trial included patients with very low- to intermediate‑risk MDS with ring sideroblasts1,2

BASELINE DISEASE CHARACTERISTICS OF PATIENTS IN PIVOTAL PHASE 3 MEDALIST TRIAL1,2

Demographic and
disease characteristics
REBLOZYL
(n = 153)
Placebo
(n = 76)
Age, years
Median (min, max) 71.0 (40, 95) 72.0 (26, 91)

i

36% (83/229) of all patients in the trial were 75 years of age or older, including patients up to 95 years1,2*

Time since original MDS diagnosis,a months
Median (min, max) 44.0 (3, 421) 36.1 (4, 193)
Serum EPO (U/L) categories,b n (%)
<200 88 (57.5) 50 (65.8)
200 to 500 43 (28.1) 15 (19.7)

i

While 39% of patients had serum EPO >200 U/L, 95.2% of all patients in the trial were ESA-exposed and only 4.8% were ESA-naive (EPO >200 U/L)1,2*

>500 21 (13.7) 11 (14.5)

i
Missing 1 (0.7) 0
RBC transfusions/8 weeks over 16 weeks, n (%)
<4 units 46 (30.1) 20 (26.3)

i

57% of patients had <6 RBC units/8 weeks1*

≥4 and <6 units 41 (26.8) 23 (30.3)

i
≥6 units 66 (43.1) 33 (43.4)
Diagnosis per WHO 2016 criteria,c n (%)
MDS-RSd 135 (88.2) 65 (85.5)

i

All patients had ring sideroblasts1*

MDS/MPN-RS-T 14 (9.2) 9 (11.8)

i
Othere 4 (2.6) 2 (2.6)

i
SF3B1, n (%)
Mutated 141 (92.2) 65 (85.5)

i

The majority of patients had an SF3B1 mutation2*

Nonmutated 12 (7.8) 10 (13.2)
Missing 0 1 (1.3)
IPSS-R classification risk category, n (%)
Very low 18 (11.8) 6 (7.9)

i

All patients except 1 had very low- to intermediate-risk MDS1*

Low 109 (71.2) 57 (75)

i
Intermediate 25 (16.3) 13 (17.1)

i
High 1 (0.7) 0
  • Baseline characteristics were balanced between treatment arms2

a Time since original MDS diagnosis was defined as the number of months from the date of original diagnosis to the date of informed consent.1

b Baseline EPO was defined as the highest EPO value within 35 days of the first dose of study drug.1

c MEDALIST enrolled patients with MDS with ring sideroblasts per the WHO 2008 criteria; however, these data are based on post hoc reclassification of patients by the FDA using the WHO 2016 diagnostic criteria (MDS-RS [n = 200; 87.3%], MDS/MPN-RS-T [n = 23; 10.0%], and Other [n = 6; 2.6%]).2

d Includes MDS-RS-MLD and MDS-RS-SLD.1

e Includes MDS-EB-1, MDS-EB-2, and MDS-U, which met the criteria for inclusion of ring sideroblasts ≥15% of erythroid precursors in the bone marrow or ≥5% (but <15%) if SF3B1 mutation was present.2

*Numbers in callouts are based on the entire clinical trial population.1,2

FDA, Food and Drug Administration; MDS-EB-1, myelodysplastic syndromes with excess blasts (5%–9% in the bone marrow or 2%–4% in the blood); MDS-EB-2, myelodysplastic syndromes with excess blasts (10%–19% in the bone marrow or 5%–19% in the blood); MDS-U, myelodysplastic syndromes, unclassifiable; WHO, World Health Organization.

REBLOZYL provided substantial clinical benefit through RBC transfusion independence vs placebo1

Primary endpoint: RBC-TI ≥8 weeks during weeks 1 to 241

Primary Endpoint: RBC-TI ≥ 8 weeks during weeks 1
to 24
Primary Endpoint: RBC-TI ≥ 8 weeks during weeks 1
to 24

CI, confidence interval.

In patients requiring ≥2 RBC units/8 weeks, start REBLOZYL
after at least 2 to 3 months of an inadequate response to ESAs1,2

Primary endpoint subgroup analysis: Rates of RBC transfusion independence with REBLOZYL2

Key secondary endpoints: REBLOZYL had a significantly higher rate of RBC transfusion independence vs placebo for 12 weeks or more1

Additional endpoints: REBLOZYL provided RBC-TI vs placebo in patients with MDS-RS and MDS/MPN-RS‑T1

RBC-TI ≥8 weeks during weeks 1 to 24 by diagnosis and baseline transfusion burden in MEDALIST1

Responders/N % Response (95% CI)
REBLOZYL Placebo REBLOZYL Placebo
WHO 2016 diagnosis
MDS-RS 46/135 8/65 34.1%
(26.1, 42.7)
12.3%
(5.5, 22.8)
MDS/MPN-RS-T 9/14 2/9 64.3%
(35.1, 87.2)
22.2%
(2.8, 60.0)
Othera 3/4 0/2 75.0%
(19.4, 99.4)
0.0%
(0.0, 84.2)
Baseline RBC transfusion burden
2–3 units/8 weeksb 37/46 8/20 80.4%
(66.1, 90.6)
40.0%
(19.1, 63.9)
4–5 units/8 weeksc 15/41 1/23 36.6%
(22.1, 53.1)
4.3%
(0.1, 21.9)
≥6 units/8 weeks 6/66 1/33 9.1%
(3.4, 18.7)
3.0%
(0.1, 15.8)

aIncludes MDS-EB-1, MDS-EB-2, and MDS-U.

bIncludes patients who received 3.5 units.

cIncludes patients who received 5.5 units.

Additional analysis in patients who achieved the primary endpoint (RBC transfusion independence ≥8 weeks) with REBLOZYL

Day of mean Hgb increase of 1.5 g/dL in patients who achieved the primary endpoint (n = 58)3

Day Approximate mean Hgb increase Number of REBLOZYL responders with an Hgb measurement at first evaluation
First evaluation for Hgb 8 1.5 g/dL 24

The median peak increase in Hgb level in patients in the REBLOZYL group who achieved the primary endpoint (n = 58)3

Hgb level
Median peak increase in the Hgb level 2.55 g/dL(range, 1.0–4.1)

Analysis limitations

  • The mean values and standard errors were not calculated if the number of patients was fewer than 8 in the REBLOZYL group of patients without a response or if the number was fewer than 4 in the placebo group3
  • Hgb values that were obtained within 14 days after an RBC transfusion were censored from these analyses unless they also were within 3 days before receipt of another RBC transfusion3
  • Patients may have experienced multiple periods of response intermittently between periods without response over the 24-week assessment period and extension phase through 25 to 48 weeks2
  • All patients in both arms were eligible to receive BSC, which included RBC transfusions as needed1
  • These exploratory analyses should not be interpreted to determine treatment difference between arms in these select endpoints because of potential selection bias, insufficient sample size, and a higher probability of making a false positive finding

Additional analysis: Modified hematologic improvement‑erythroid (mHI-E) was assessed in patients receiving REBLOZYL

mHI-E was defined per the IWG criteria as the proportion of patients who met mHI-E criteria sustained over any consecutive 56-day (8 week) period2:

  • For patients with baseline RBC transfusion burden of at least 4 units/8 weeks: response was defined as a reduction in RBC transfusion burden of ≥4 RBC units/8 weeks
  • For patients with baseline RBC transfusion burden of less than 4 units/8 weeks: response was defined as a mean Hgb increase of ≥1.5 g/dL/8 weeks in the absence of transfusions for at least 8 weeks

MODIFIED HEMATOLOGIC IMPROVEMENT-ERYTHROID (mHI-E) IN PATIENTS RECEIVING REBLOZYL VS PLACEBO2

Weeks 1–24 Weeks 1–48
REBLOZYL
(n = 153)
Placebo
(n = 76)
REBLOZYL
(n = 153)
Placebo
(n = 76)
Modified hematologic improvement-erythroid (mHI-E) 52.9%
(81/153)
11.8%
(9/76)
58.8%
(90/153)
17.1%
(13/76)
RBC transfusion reduction of ≥4 units/8 weeksa 48.6%
(52/107)
14.3%
(8/56)
54.2%
(58/107)
21.4%
(12/56)
Mean Hgb increase of ≥1.5 g/dL for 8 weeks in the absence of transfusionsb 63.0%
(29/46)
5.0%
(1/20)
69.6%
(32/46)
5.0%
(1/20)

aPercentage based on number of patients with baseline RBC transfusion burden of ≥4 units/8 weeks (n = 107 in the REBLOZYL arm).

bPercentage based on number of patients with baseline RBC transfusion burden of <4 units/8 weeks (n = 46 in the REBLOZYL arm).

Analysis limitations

  • The primary endpoint of the study was transfusion independence defined as the absence of any RBC transfusion during any consecutive 8-week period occurring within weeks 1 through 241
    • Primary endpoint data: 37.9% (58/153) for REBLOZYL vs 13.2% (10/76) for placebo
  • The mHI-E analysis is a broader analysis than transfusion independence. The analysis included patients that did not meet the primary endpoint of transfusion independence2:
    • Those who achieved transfusion reduction of ≥4 units over 8 weeks (with higher baseline transfusion burden)
    • Those whose Hgb increased by ≥1.5 g/dL for 8 weeks in the absence of transfusions (with lower baseline transfusion burden)
  • Patients may have experienced multiple periods of response intermittently between periods without response over the 24-week assessment period and extension phase through 25 to 48 weeks2
  • All patients in both arms were eligible to receive BSC, which included RBC transfusions as needed1
  • These exploratory analyses should not be interpreted to determine treatment difference between arms in these select endpoints because of potential selection bias, insufficient sample size, and a higher probability of making a false positive finding
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Indication

REBLOZYL is indicated for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions.

REBLOZYL is indicated for the treatment of anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).

REBLOZYL is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Thrombosis/Thromboembolism

In adult patients with beta thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) REBLOZYL-treated patients. TEEs included deep vein thrombosis, pulmonary embolus, portal vein thrombosis, and ischemic stroke. Patients with known risk factors for thromboembolism (splenectomy or concomitant use of hormone replacement therapy) may be at further increased risk of thromboembolic conditions. Consider thromboprophylaxis in patients at increased risk of TEE. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly.

Hypertension

Hypertension was reported in 10.7% (61/571) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3 to 4 hypertension ranged from 1.8% to 8.6%. In patients with beta thalassemia with normal baseline blood pressure, 13 (6.2%) patients developed systolic blood pressure (SBP) ≥130 mm Hg and 33 (16.6%) patients developed diastolic blood pressure (DBP) ≥80 mm Hg. In adult patients with MDS with normal baseline blood pressure, 26 (29.9%) patients developed SBP ≥130 mm Hg and 23 (16.4%) patients developed DBP ≥80 mm Hg. Monitor blood pressure prior to each administration. Manage new or exacerbations of preexisting hypertension using anti-hypertensive agents.

Embryo-Fetal Toxicity

REBLOZYL may cause fetal harm when administered to a pregnant woman. REBLOZYL caused increased post-implantation loss, decreased litter size, and an increased incidence of skeletal variations in pregnant rat and rabbit studies. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the final dose.

ADVERSE REACTIONS

Beta-Thalassemia

  • Serious adverse reactions occurred in 3.6% of patients on REBLOZYL. Serious adverse reactions occurring in 1% of patients included cerebrovascular accident and deep vein thrombosis. A fatal adverse reaction occurred in 1 patient treated with REBLOZYL who died due to an unconfirmed case of acute myeloid leukemia (AML)
  • Most common adverse reactions (at least 10% for REBLOZYL and 1% more than placebo) were headache (26% vs 24%), bone pain (20% vs 8%), arthralgia (19% vs 12%), fatigue (14% vs 13%), cough (14% vs 11%), abdominal pain (14% vs 12%), diarrhea (12% vs 10%) and dizziness (11% vs 5%)

Myelodysplastic Syndromes

  • Grade ≥3 (≥2%) adverse reactions included fatigue, hypertension, syncope and musculoskeletal pain. A fatal adverse reaction occurred in 5 (2.1%) patients
  • The most common (≥10%) adverse reactions included fatigue, musculoskeletal pain, dizziness, diarrhea, nausea, hypersensitivity reactions, hypertension, headache, upper respiratory tract infection, bronchitis, and urinary tract infection

LACTATION

It is not known whether REBLOZYL is excreted into human milk or absorbed systemically after ingestion by a nursing infant. REBLOZYL was detected in milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because many drugs are excreted in human milk, and because of the unknown effects of REBLOZYL in infants, a decision should be made whether to discontinue nursing or to discontinue treatment. Because of the potential for serious adverse reactions in the breastfed child, breastfeeding is not recommended during treatment and for 3 months after the last dose.

Please click here for full Prescribing Information for REBLOZYL.

References: 1. REBLOZYL [Prescribing Information]. Summit, NJ: Celgene Corporation; 2020. 2. Data on file. Celgene Corporation. Summit, New Jersey. 3. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382(2):140-151.