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Know the facts when diagnosing MDS-RS

Proper testing plays a role in treatment decisions1

  • REBLOZYL is approved for patients with MDS-RS who are failing an ESA and require ≥2 RBC units/8 weeks2

The importance of ring sideroblasts in diagnosing MDS

23% to 33% of patients with MDS have ring sideroblasts23% to 33% of patients with MDS have ring sideroblasts

  • Ring sideroblasts at any level are part of the diagnosis of certain subtypes of MDS1,4
  • The quantification of ring sideroblasts by pathologists is important for MDS-RS classification and for treatment decisions1
  • The WHO classification of MDS indicates that the proportion of ring sideroblasts and the presence of an SF3B1 mutation are needed for the diagnosis and classification of the MDS-RS subtypes1

Classification of MDS‑RS can be made based on the following criteria1:

  • ≥15% ring sideroblasts or
  • ≥5% ring sideroblasts with an SF3B1 mutation

Ring sideroblasts can also be present in MDS/MPN-RS-T, which is a rare subtype recognized by the WHO 2016. It has similarities to MDS‑RS but is characterized by specific clinical features1,5

  • These include anemia, bone marrow dysplasia with ring sideroblasts, and persistent thrombocytosis ≥450 × 109/L with proliferation of large and morphologically atypical megakaryocytes1

MDS, myelodysplastic syndromes; MDS/MPN-RS-T, myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis; MDS-RS, MDS with ring sideroblasts; WHO, World Health Organization.

Ring sideroblasts can be evaluated using a bone marrow aspirate, a blood clot (from a bone aspirate), or a bone marrow trephine biopsy6

Ring sideroblasts in bone marrow

For illustrative purposes only.

Methods to assess ring sideroblasts in cases with inadequate particles on aspirate for iron staining:

  • In situations where a bone marrow aspirate is inadequate due to being aparticulate, it may not be possible to make an accurate assessment of ring sideroblasts
  • If the bone marrow aspirate is aparticulate, iron staining for ring sideroblasts can also be performed on a blood clot or a bone marrow trephine biopsy7

Bone marrow smear demonstrating ring sideroblasts

Bone marrow smear with ring sideroblasts

Bone marrow trephine biopsy demonstrating RS

Bone marrow trephine biopsy demonstrating RS (ring sideroblasts)

Blood clot from a bone marrow aspirate demonstrating RS

Blood clot from a bone marrow aspirate demonstrating RS (ring sideroblasts)

Inadequate/particulate bone marrow smear

Inadequate/particulate bone marrow smear

RS, ring sideroblasts.

A pathologist's quantitative assessment of ring sideroblasts and SF3B1 mutation status is critical to diagnosing patients with MDS‑RS1,8

Chart identifying patients' ring sideroblast percentages for Reblozyl®
Chart identifying patients' ring sideroblast percentages for Reblozyl®

REBLOZYL is approved for patients with MDS-RS who are failing an ESA and require ≥2 RBC units/8 weeks2

There is currently a degree of variability in how pathologists describe the presence of ring sideroblasts in pathology reports9

  • Ring sideroblasts quantification should be included on the lab report in addition to the assessment of SF3B1 mutation status1
  • Quantitative reporting is critical to identifying patients with MDS-RS. REBLOZYL is approved specifically for patients with MDS-RS associated anemia1,2,7
  • Variability in reporting of bone marrow specimens may result in incomplete or misleading information9

ESA, erythropoiesis-stimulating agent.

There is a strong link between MDS‑RS, MDS/MPN-RS-T,
and an SF3B1 mutation1

Bar chart showing percentage of patients with SF3B1 mutation
Bar chart showing percentage of patients with SF3B1 mutation

The presence of an SF3B1 mutation and RS ≥5% could identify a diagnosis of MDS-RS and indicate the patient may be eligible for REBLOZYL therapy1,2

A range of different technologies can be used by pathologists to test for SF3B1 mutations

Pathology technologies chart

cDNA, complementary DNA; ddPCR, droplet digital PCR; DNA, deoxyribonucleic acid; NGS, next generation sequencing; PCR, polymerase chain reaction; TATs, turnaround times.

Expand

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.

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 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

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.

Indication

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 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

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. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. 2. REBLOZYL [Prescribing Information]. Summit, NJ: Celgene Corporation; 2020. 3. Papaemmanuil E, Gerstung M, Malcovati L, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122(22):3616-3627. 4. Malcovati L, Cazzola M. Recent advances in the understanding of myelodysplastic syndromes with ring sideroblasts. Br J Haematol. 2016;174(6):847-858. 5. Aoyama Y, Sakai K, Kodaka T, et al. Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN with RS-T) complicated by hyperleukocytosis and gene analysis in relation to leukocytosis. J Clin Exp Hematop. 2019;59(1):29-33. 6. Fenaux P, Haase D, Sanz GF, Santini V, Buske C; ESMO Guidelines Working Group. Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(suppl3):iii57-iii69. doi:10.1093/annonc/mdu18. 7. Lee SH, Erber WN, Portwit A, Tomonaga M, Peterson C; International Council for Standardization in Hematology. ICSH guidelines for the standardization of bone marrow specimens and reports. Int J Lab Hematol. 2008;30(5):349-364. 8. Kubasch AS, Fenaux P, Platzbecker U. Development of luspatercept to treat ineffective erythropoiesis. Blood Adv. 2021;5(5):1565-1575. 9. Sever C, Abbott CL, de Baca ME. Bone marrow synoptic reporting for hematologic neoplasms: guideline from the College of American Pathologists Pathology and Laboratory Quality Center. Arch Pathol Lab Med. 2016;140(9):932-949. 10. Malcovati L, Papaemmanuil E, Bowen DT, et al; Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium and of the Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood. 2011;118(24):6239-6246. 11. Taylor SC, Laperriere L, Germain H. Droplet Digital PCR versus qPCR for gene expression analysis with low abundant targets: from variable nonsense to publication quality data. Sci Rep. 2017;7(1):2409. doi: 10.1038/s41598-017-02217-x. 12. Sherwood JL, Brown H, Rettino A, et al. Key differences between 13 KRAS mutation detection technologies and their relevance for clinical practice. ESMO Open. 2017;2(4):e000235. 13. Arya M, Shergill I, Williamson M, Gommersall L, Arya N, Patel HRH. Basic principles of real-time quantitative PCR. Expert Rev Mol Diagn. 2005;5(2):209-219. 14. Pollyea DA, George TI, Abedi M, et al. Diagnostic and molecular testing patterns in patients with newly diagnosed acute myeloid leukemia in the Connect® MDS/AML Disease Registry. eJHaem. 2020;1:58-68. doi: 10.1002/jha2.16. 15. Qin D. Next-generation sequencing and its clinical application. Cancer Biol Med. 2019;16(1):4-10. doi: 10.20892/j.issn.2095-3941.2018.0055. 16. Aguilera-Diaz A, Vazquez I, Ariceta B, et al. Assessment of the clinical utility of four NGS panels in myeloid malignancies. Suggestions for NGS panel choice or design. PLoS One. 2020;15(1):e0227986. 17. Spaulding TP, Stockton SS, Savona MR. The evolving role of next generation sequencing in myelodysplastic syndromes. Br J Haematol. 2020;188(2):224-239.