MDS: Diagnostic Criteria and Risk Stratification Full abbreviations, accreditation, and disclosure information available at PeerView.com/MDS-Live

Diagnosis Criteria and Differential Diagnosis of MDS1

MDS “Decisive” Criteria Cytopenia(s) • >10% dysplastic cells in one or more lineages, or • Hb <11 g/dL, or • 5%-19% blasts, or • ANC <1,500/mcL, or + • Abnormal karyotype typical for MDS, or • Platelets <100 x 109/L • Evidence of clonality + EXCLUDE Other Causes of Cytopenias and Morphological Changes • / deficiency • HIV or other viral infection • Copper deficiency • Alcohol abuse • (especially methotrexate, azathioprine, recent chemotherapy) • Autoimmune conditions (ITP, Felty syndrome, SLE, etc.) • Congenital syndromes (Fanconi , etc.) • Other hematological disorders (aplastic anemia, LGL disorders, MPN, etc.)

Understanding the Risk in MDS

• The risk of MDS refers often to risk of mortality and AML transformation • Knowing the risk provides prognostic information for the patients, caregivers, and treating physicians • Risk stratification serves as a decision tool to tailor therapy – Allogeneic stem cell transplantation – Disease-altering therapies

Consider complete cytogenetics and NGS panel for all patients with MDS to understand the risk level MDS: Diagnostic Criteria and Risk Stratification Full abbreviations, accreditation, and disclosure information available at PeerView.com/MDS-Live

Revised International Prognostic Scoring System (IPSS-R)2,3

IPSS-R Cytogenetic Score

Prognostic Subgroups Cytogenetic Abnormalities

Very good -Y, del(11q)

Good Normal, del(5q), del(12p), del(20q), double incl. del(5q)

Intermediate del(7q), +8, +19, i(17q), any other single or double independent clones

-7, inv(3)/t(3q), del3q, double including -7/del(7q), Poor Complex: 3 abnormalities

Very poor Complex: >3 abnormalities

IPSS-R Prognostic Score Values

Prognostic 0 0.5 1 1.5 2 3 4 Variable Very Cytogenetics Very good – Good – Intermediate Poor (refer to the table above) poor Bone marrow ≤2 – >2 - <5 – 5-10 >10 – blasts, %

Hemoglobin ≥10 – 8 - <10 <8 – – –

Platelets ≥100 50 - <100 <50 – – – –

ANC ≥0.8 <0.8 – – – – –

IPSS-R Overall Median Survival in 25% AML Progression in Absence Risk Category Score Absence of Therapy, y of Therapy, y

Very low ≤1.5 8.8 NR

Low >1.5 - ≤3.0 5.3 10.8

Int3 >3.0 - ≤4.5 3.0 3.2 High >4.5 - ≤6.0 1.6 1.4 Very high >6.0 0.8 0.7 MDS: Diagnostic Criteria and Risk Stratification Full abbreviations, accreditation, and disclosure information available at PeerView.com/MDS-Live

WHO Classification System for MDS3,a,b

Subtype Bone Marrow

MDS with single-lineage Single or bicytopenia Dysplasia in ≥10% of 1 cell line, <5% blastsd dysplasiac ≥15% of erythroid precursors with ring MDS with ring Anemia, no blasts sideroblasts, or ≥5% ring sideroblasts sideroblasts if SF3B1 mutation present Dysplasia in ≥10% of cells in ≥2 hematopoietic MDS with multilineage Cytopenias, lineages, <15% ring sideroblasts dysplasia <1 x 109/L monocytes (or <5% ring sideroblasts if SF3B1 mutation present), <5% blasts Cytopenias, Unilineage or multilineage dysplasia, MDS with excess blasts-1 ≤2% - 4% blasts, 5%-9% blasts, no Auer rods <1 x 109/L monocytes Cytopenias, Unilineage or multilineage dysplasia, MDS with excess blasts-2 5% - 19% blasts, 10%-19% blasts, ± Auer rods <1 x 109/L monocytes Cytopenias, ±1% blasts Unilineage dysplasia or no dysplasia but MDS unclassifiable on at least 2 occasions characteristic MDS cytogenetics, <5% blasts Unilineage erythroid dysplasia, isolated Anemia, platelets MDS with isolated del(5q) del(5q), <5% blasts ± 1 other abnormality normal or increased except -7/del(7q) Refractory cytopenia of childhood (provisional Cytopenias, <2% blasts Dysplasia in 1-3 lineages, <5% blasts WHO category)

a 2016 WHO classification for AML includes entity "AML with myelodysplasia-related changes" that encompasses pts previously categorized in the FAB classification of MDS as RAEB-T. AML evolving from MDS (AML-MDS) is often more resistant to cytotoxic chemotherapy than AML that arises without antecedent hematologic disorder and may have more indolent course. Some clinical trials designed for high-grade MDS may allow enrollment of pts with AML-MDS. Pts with 20%-29% marrow blasts and stable clinical course for at least 2 mo may be considered as either MDS or AML and may be more akin to MDS (prior FAB RAEB-T) than to AML. Such patients may be considered for treatment as either MDS or AML. Individuals with FLT3 and NPM1 mutations are more likely to have AML than MDS. b WHO classification notes that a subgroup of pts have therapy-related MDS, with may include any of the subtypes listed here. These patients tend to have poor-risk cytogenetics and many cases have demonstrated germline mutations in cancer susceptibility genes. c This category encompasses refractory anemia (RA), refractory neutropenia (RN), and refractory thrombocytopenia (RT). Cases of RN and RT were previously classified as MDS unclassified. d Per WHO classification for MDS, the threshold for cell line dysplasia is ≥10% for myeloid and erythroid lineages; for megakaryocytes, a threshold of approximately 30%-40% may provide improved specificity.

1. Valent P et al. Leuk Res. 2007;31:727-736. 2. https://www.aamds.org/support/mds-toolkit. 3. NCCN Clinical Practice Guidelines in Oncology: Myelodysplastic Syndromes. Version 1.2021. https://www.nccn. org/professionals/physician_gls/pdf/mds.pdf. The Aplastic Anemia and MDS International Foundation (AAMDSIF) Patient Resources Full abbreviations, accreditation, and disclosure information available at PeerView.com/MDS-Live

What Is MDS?1

Myelodysplastic syndromes is the name for a group of different conditions that affect your bone marrow and blood. Bone marrow is inside your bones and is where all your blood cells are made. MDS stops your bone marrow from making healthy blood cells (red blood cells, white blood cells, and/or platelets). The blood cells are not normal, meaning they are immature, may not be normal in shape/ size, and stay inside the marrow instead of going out into the blood.

MDS is a group of diseases, not just one disease. Symptoms vary widely depending on which of your three types of blood cells are affected. • Red blood cells carry oxygen from your lungs to all the cells in your body. • White blood cells protect you by attacking germs. There are many different types of white cells to fight different germs. • Platelets help your blood clot and stop bleeding.

People with MDS always have a low level of at least 1 of the 3 types of blood cells, called a cytopenia. These abnormal cells do not function properly.

Key Facts1

• MDS is the name for a group of different conditions that affects blood cells and bone marrow • In most cases the cause of MDS is not known • MDS stops your body from making healthy red blood cells, white blood cells, and/or platelets. Instead, your body makes blood cells that aren’t normal in appearance and can be immature (not fully grown) The Aplastic Anemia and MDS International Foundation (AAMDSIF) Patient Resources Full abbreviations, accreditation, and disclosure information available at PeerView.com/MDS-Live

Who Develops MDS?2,3

• Men: Little more common in men than women • Age 60 or older • In the United States, >10,000 people are diagnosed with MDS per year

What Causes MDS?2,3

Risk factors: approximately 90% occur de novo with no identifiable cause • De novo – Cigarette smoking – Ionizing radiation – Organic solvents (benzene, toluene, xylene, chloramphenicol) – Heavy metals – Herbicides, pesticides, fertilizers • Secondary MDS – Chemotherapy with alkylating agents Presentation • Clinical symptoms of pancytopenia (anemia, bleeding, easy bruising, fatigue) • Lab abnormalities: macrocytosis, neutropenia, thrombocytopenia, anemia, signs of hemolysis due to ineffective erythropoiesis

MDS Toolkit1 Additional AAMDSIF Resources1 ü Disease information pages ü Patient education booklets and fact sheets ü Patient counselling aids ü Webinars ü Healthcare management tools ü Research updates ü Treatment trackers ü Peer support network and support groups

1. www.aamds.org. 2. Du Y et al. Leuk Res. 2010;34:1-5. 3. Strom SS et al. Leukemia. 2005;19:1912-1918. Currently Approved and Emerging Investigational Therapies in MDS Full abbreviations, accreditation, and disclosure information available at PeerView.com/MDS-Live

Currently Approved Therapies for MDS in the United States

ASTX727 (cedazuridine + decitabine) IPSS 1997 Lenalidomide FDA approval 2005 Improved FDA approval 2020 cytogenetic classi cation Cytogenetics 1970; Chromosomes in Decitabine leukemia 1979 Azacitidine FDA approval 2006 Luspatercept FDA approval 2004 Application of FDA approval NGS in MDS 2020 ???

1970s 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2019 2020 2021

Erythropoiesis stimulating agents often used but not FDA approved Currently Approved and Emerging Investigational Therapies in MDS Full abbreviations, accreditation, and disclosure information available at PeerView.com/MDS-Live

Currently Approved Therapies for MDS in the United States

Azacitidine for injection1 Dosing WARNING Initial US approval: 2004 • The recommended starting dose for the first • Anemia, neutropenia, and thrombocytopenia treatment cycle, for all patients regardless Indications and Usage in MDS • Hepatotoxicity of baseline hematology values, is 75 mg/m2 Nucleoside metabolic inhibitor indicated for the daily for 7 d via subQ injection or IV infusion. • Renal abnormalities treatment of patients with the following FAB Premedicate for nausea and vomiting MDS subtypes: • Monitor liver chemistries and serum • Repeat cycles every 4 wk. After 2 cycles, may creatinine prior to initiation of therapy and • Refractory anemia or refractory anemia increase dose to 100 mg/m2 if no beneficial with each cycle with ringed sideroblasts (if accompanied by effect is seen and no toxicity other than nausea neutropenia or thrombocytopenia or requiring • May cause fetal harm when administered to and vomiting has occurred. Patients should be transfusions) a pregnant woman. Women of childbearing treated for a minimum of 4-6 cycles. Complete potential should be apprised of the potential • Refractory anemia with excess blasts or partial response may require additional hazard to a fetus. Men should be advised not • Refractory anemia with excess blasts in treatment cycles to father a child while receiving therapy transformation • Continue treatment as long as the patient Adverse Events • CMML continues to benefit • Most common (>30%) by subQ route: nausea, • Patients should be monitored for hematologic anemia, thrombocytopenia, vomiting, pyrexia, response and renal toxicities, with dosage leukopenia, diarrhea, injection-site erythema, delay or reduction as appropriate constipation, neutropenia, and ecchymosis • Most common by IV route also included petechiae, rigors, weakness, and hypokalemia

Lenalidomide capsules2 WARNING Initial US approval: 2005 • Embryo-fetal toxicity Indications and Usage in MDS • Hematologic toxicity Transfusion-dependent anemia due to low- or intermediate-1–risk MDS • Venous and arterial thromboembolism associated with a del(5q) abnormality with or without additional cytogenetic abnormalities Adverse Events Dosing • Most common (>15%) include thrombocytopenia, neutropenia, diarrhea, 10 mg once daily pruritus, rash, fatigue, constipation, nausea, nasopharyngitis, arthralgia, pyrexia, back pain, peripheral edema, cough, dizziness, headache, muscle cramp, dyspnea, pharyngitis, and epistaxis Currently Approved and Emerging Investigational Therapies in MDS Full abbreviations, accreditation, and disclosure information available at PeerView.com/MDS-Live

Currently Approved Therapies for MDS in the United States

Decitabine for injection3 Dosing Initial US approval: 2006 • 3-d regimen: administer 15 mg/m2 continuous IV infusion over 3 h repeated every 8 h for 3 d . Repeat cycle every 6 wk Indications and Usage in MDS Nucleoside metabolic inhibitor indicated for treatment of adult patients with • 5-d regimen: administer 20 mg/m2 continuous IV infusion over 1 h repeated MDS including previously treated and untreated, de novo, and secondary MDS daily for 5 d. Repeat cycle every 4 wk of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia WARNING with excess blasts in transformation, and chronic myelomonocytic leukemia) and • Neutropenia and thrombocytopenia intermediate-1, intermediate-2, and high-risk IPSS groups • Embryo-fetal toxicity

Adverse Events • Most common (>50%): neutropenia, thrombocytopenia, anemia, and pyrexia

Luspatercept-aamt for injection4 WARNING Initial US approval: 2019 • Thrombosis/thromboembolism: increased risk in patients with β-thalassemia. Indications and Usage in MDS Monitor patients for signs and symptoms of thromboembolic events and Luspatercept is an erythroid maturation agent indicated for the treatment of institute treatment promptly anemia failing an ESA and requiring 2 or more RBC units over 8 wk in adult • Hypertension: monitor BP during treatment; initiate anti-hypertensive patients with very low- to intermediate-risk MDS with ring sideroblasts or treatment if necessary with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and • Embryo-fetal toxicity: may cause fetal harm; advise females of reproductive thrombocytosis potential of the potential risk to a fetus and use of effective contraception Limitations of Use: Not indicated for use as a substitute for RBC transfusions in Adverse Events patients who require immediate correction of anemia • Most common (>10%): fatigue, headache, musculoskeletal pain, arthralgia, dizziness/vertigo, nausea, diarrhea, cough, abdominal pain, dyspnea, and Dosing hypersensitivity • The recommended starting dose is 1 mg/kg Q3W by subQ injection • Review Hb results prior to each administration • See full prescribing information for preparation and administration instructions Currently Approved and Emerging Investigational Therapies in MDS Full abbreviations, accreditation, and disclosure information available at PeerView.com/MDS-Live

Currently Approved Therapies for MDS in the United States

ASTX727 (decitabine and cedazuridine) tablets5 WARNING Initial US approval: 2020 • Myelosuppression: fatal and serious myelosuppression and infectious complications can occur. Obtain complete blood cell counts prior to initiation, Indications and Usage in MDS prior to each cycle, and as clinically indicated to monitor for response and Combination of decitabine (nucleoside metabolic inhibitor) and cedazuridine toxicity. Delay the next cycle and resume at the same or reduced dose as (cytidine deaminase inhibitor), indicated for treatment of adult patients with recommended MDS, including previously treated and untreated, de novo, and secondary MDS with the following FrenchAmerican-British subtypes (refractory anemia, • Embryo-fetal toxicity: can cause fetal harm. Advise patients of reproductive refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, potential of the potential risk to a fetus and to use effective contraception and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk IPSS groups Adverse Events • Most common (≥20%): fatigue, constipation, hemorrhage, myalgia, mucositis, Dosing arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, • Recommended dosage of is 1 tablet (35 mg decitabine and 100 mg edema, headache, cough, decreased appetite, URTI, pneumonia, and cedazuridine) taken orally once daily on d 1-5 of each 28-d cycle transaminase increased • Take on an empty stomach • Most common grade 3/4 laboratory abnormalities (≥50%): leukocytes decreased, platelet count decreased, neutrophil count decreased, and Hb decreased Currently Approved and Emerging Investigational Therapies in MDS Full abbreviations, accreditation, and disclosure information available at PeerView.com/MDS-Live

Selected Phase 3/4 Trials in MDS: Targeted Therapies and Novel Combinations6

NCT Number Study Title Conditions Interventions Status

Study of AG-120 (Ivosidenib) vs. Placebo in Combination With Azacitidine AML; newly diagnosed AG-120 (ivosidenib) with NCT03173248 in Patients With Previously Untreated Acute Myeloid Leukemia With AML; untreated AML; azacitidine; placebo with Recruiting an IDH1 Mutation AML arising from MDS azacitidine

Efficacy and Safety Study of Luspatercept (ACE-536) Versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low, Low or Intermediate Risk NCT03682536 MDS Luspatercept; epoetin alfa Recruiting Myelodysplastic Syndromes (MDS) in ESA Naïve Subjects Who Require Red Blood Cell Transfusions

APR-246 & Azacitidine for the Treatment of TP53 Mutant Myelodysplastic APR-246 + azacitidine; Active, NCT03745716 MDS Syndromes (MDS) azacitidine not recruiting

Active, A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or NCT02631070 MDS Luspatercept; placebo not recruiting Intermediate Risk Myelodysplastic Syndromes Has results

MDS; CML; AML; Azacitidine; ASTX030 A Study of ASTX030 (Cedazuridine in Combination With Azacitidine) in MDS, NCT04256317 myelodysplastic (cedazuridine + Recruiting CMML, or AML syndrome/neoplasm azacitidine); cedazuridine

Guadecitabine (SGI-110) vs Treatment Choice in Adults With MDS or CMML Guadecitabine; treatment Active, NCT02907359 MDS; CMML Previously Treated With HMAs choice not recruiting

The Efficacy and Safety of Oral Azacitidine Plus Best Supportive Care Versus Placebo and Best Supportive Care in Subjects With Red Blood Active, Oral azacitidine; placebo; NCT01566695 Cell (RBC) Transfusion-Dependent Anemia and Thrombocytopenia Due MDS not recruiting best supportive care to International Prognostic Scoring System (IPSS) Low Risk Myelodysplastic Has results Syndrome (MDS) Currently Approved and Emerging Investigational Therapies in MDS Full abbreviations, accreditation, and disclosure information available at PeerView.com/MDS-Live

Selected Phase 3/4 Trials in MDS: Targeted Therapies and Novel Combinations6

NCT Number Study Title Conditions Interventions Status

ASTX727; NCT03306264 Study of ASTX727 vs IV Decitabine in MDS, CMML, and AML MDS; CMML; AML Recruiting decitibine

Study to Evaluate Imetelstat (GRN163L) in Subjects With International Prognostic Imetelstat; NCT02598661 MDS Recruiting Scoring System (IPSS) Low or Intermediate-1 Risk (MDS) placebo

Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS), Azacitidine; Active, NCT03268954 MDS; CMML; AML Chronic Myelomonocytic Leukemia (CMML), or Low-Blast Acute pevonedistat not recruiting Myelogenous Leukemia (AML)

Study of REVLIMID (Lenalidomide) Versus Placebo in Patients With Low Risk Lenalidomide; Active, NCT01243476 MDS Myelodysplastic Syndrome placebo not recruiting

Magrolimab + Azacitidine Versus Azacitidine + Placebo in Untreated Participants Magrolimab; NCT04313881 MDS Recruiting With Myelodysplastic Syndrome (MDS) azacitidine; placebo

MDS; β-thalassemia; A Study to Evaluate Long-term Safety in Subjects Who Have Participated in Other NCT04064060 MPN-associated Luspatercept Recruiting Luspatercept (ACE-536) Clinical Trials myelofibrosis

Safety And Efficacy Study Of Venetoclax Tablet With Intravenous or Subcutaneous Venetoclax; NCT04401748 Azacitidine to Assess Change in Complete Remission and Overall Survival In Adult MDS Recruiting azacitidine; placebo Participants With Newly Diagnosed Higher-Risk Myelodysplastic Syndrome

1. Vidaza (azacitidine) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050794s011lbl.pdf. 2. Revlimid (lenalidomide) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021880s034lbl.pdf. 3. Dacogen (decitibine) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021790s021lbl.pdf. 4. Reblozyl (luspatercept-aamt) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761136lbl.pdf. 5. Inqovi (decitabine and cedazuridine) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212576s000lbl.pdf. 6. clinicaltrials.gov.