Diagnostic Criteria and Differential Diagnosis of MDS

MDS: Diagnostic Criteria and Risk Stratification

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Diagnostic Criteria and Differential Diagnosis of MDS1

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Understanding Risk in MDS

Cytopenia(s)

• Hb <11 g/dL, or

• ANC <1,500/mcL, or

• Platelets <100 x 109/L

MDS “Decisive” Criteria

• >10% dysplastic cells in one or more lineages, or

• 5%-19% blasts, or

• Abnormal karyotype typical for MDS, or

• Evidence of clonality

EXCLUDE Other Causes of Cytopenias and Morphological Changes

• Vitamin B12/folate deficiency

• HIV or other viral infection

• Copper deficiency

• Alcohol abuse

• Medications (especially methotrexate, azathioprine, recent chemotherapy)

• Autoimmune conditions (eg, ITP, Felty syndrome, SLE)

• Congenital syndromes (eg, Fanconi anemia)

• Other hematologic disorders (eg, aplastic anemia, LGL disorders, MPN)

• Risk in MDS refers often to risk of mortality and AML transformation

• Understanding 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

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

IPSS-R Cytogenetic Score

IPSS-R Prognostic Score Values

Prognostic Subgroups Cytogenetic Abnormalities

Very good -Y, del(11q)

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

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

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

Very poor Complex: >3 abnormalities

Prognostic Variable 0 0.5 1 1.5 2 3 4

Cytogenetics(refer to the table above) Very good – Good – Intermediate Poor Very

poor

Bone marrow blasts, % ≤2 – >2 - <5 – 5-10 >10 –

Hemoglobin ≥10 – 8 - <10 <8 – – –

Platelets ≥100 50 - <100 <50 – – – –

ANC ≥0.8 <0.8 – – – – –

IPSS-RRisk Category

Overall Score

Median Survival in Absence of Therapy, y

25% AML Progression in Absence of Therapy, y

Very low ≤1.5 8.8 NR

Low >1.5 - ≤3.0 5.3 10.8

Intermediate >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




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.

WHO Classification System for MDS3,a,b

Subtype Blood Bone Marrow

MDS with single-lineage dysplasiac Single or bi-cytopenia Dysplasia in ≥10% of 1 cell line, <5% blastsd

MDS with ring sideroblasts Anemia, no blasts

≥15% of erythroid precursors with ring sideroblasts, or ≥5% ring sideroblasts

if SF3B1 mutation present

MDS with multilineage dysplasia

Cytopenias, <1 x 109/L monocytes

Dysplasia in ≥10% of cells in ≥2 hematopoietic lineages, <15% ring sideroblasts

(or <5% ring sideroblasts if SF3B1 mutation present), <5% blasts

MDS with excess blasts-1Cytopenias,

≤2%-4% blasts, <1 x 109/L monocytes

Unilineage or multilineage dysplasia, 5%-9% blasts, no Auer rods

MDS with excess blasts-2Cytopenias,

5%-19% blasts,<1 x 109/L monocytes

Unilineage or multilineage dysplasia, 10%-19% blasts, ± Auer rods

MDS unclassifiable Cytopenias, ±1% blasts on at least 2 occasions

Unilineage dysplasia or no dysplasia but characteristic MDS cytogenetics, <5% blasts

MDS with isolated del(5q) Anemia, platelets normal or increased

Unilineage erythroid dysplasia, isolated del(5q), <5% blasts ± 1 other abnormality

except -7/del(7q)

Refractory cytopenia of childhood (provisional WHO category)

Cytopenias, <2% blasts Dysplasia in 1-3 lineages, <5% blasts


The Aplastic Anemia and MDS International Foundation (AAMDSIF)

Patient Resources Full abbreviations, accreditation, and disclosure information available at

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What Is MDS?1

Key Facts1

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.

• 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/ZAW40

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.

Who Develops MDS?2,3

What Causes MDS?2,3

• Men: slightly more common in men than women

• Age 60 or older

• In the United States, >10,000 people are diagnosed with MDS per year

MDS Toolkit1

üDisease information pages

üPatient counseling aids

üHealthcare management tools

üTreatment trackers

Additional AAMDSIF Resources1

üPatient education booklets and fact sheets

üWebinars

üResearch updates

üPeer support network and support groups

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


Currently Approved and Emerging Investigational Therapies in MDS


Currently Approved Therapies for MDS in the United States

Erythropoiesis stimulating agents often used but not FDA approved

Cytogenetics 1970;Chromosomes inleukemia 1979

IPSS 1997 LenalidomideFDA approval 2005

AzacitidineFDA approval 2004

DecitabineFDA approval 2006

ASTX727 (cedazuridine + decitabine)FDA approval 2020

LuspaterceptFDA approval2020 ???

Improvedcytogeneticclassi�cation

Application ofNGS in MDS

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




Azacitidine for injection1 Initial US approval: 2004

Indications and Usage in MDS Nucleoside metabolic inhibitor indicated for the treatment of patients with the following FAB MDS subtypes:

• Refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions)

• Refractory anemia with excess blasts

• Refractory anemia with excess blasts in transformation

• CMML

Dosing • The recommended starting dose for the first

treatment cycle, for all patients regardless of baseline hematology values, is 75 mg/m2 daily for 7 d via subQ injection or IV infusion. Premedicate for nausea and vomiting

• Cycles should be repeated every 4 wk. After 2 cycles, may increase dose to 100 mg/m2 if no beneficial effect is seen and no toxicity other than nausea and vomiting has occurred. Patients should be treated for a minimum of 4-6 cycles. Complete or partial response may require additional treatment cycles

• Continue treatment as long as the patient continues to benefit

• Patients should be monitored for hematologic response and renal toxicities, with dosage delay or reduction as appropriate

WARNING • Anemia, neutropenia, and thrombocytopenia

• Hepatotoxicity

• Renal abnormalities

• Monitor liver chemistries and serum creatinine prior to initiation of therapy and with each cycle

• Azacitidine may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be apprised of the potential hazard to a fetus. Men should be advised not to father a child while receiving therapy

Adverse Events • Most common (>30%) by subQ route: nausea,

anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection-site erythema, constipation, neutropenia, and ecchymosis

• Most common by IV route also included petechiae, rigors, weakness, and hypokalemia

Lenalidomide capsules2 Initial US approval: 2005

Indications and Usage in MDS Transfusion-dependent anemia due to low- or intermediate-1–risk MDS associated with a del(5q) abnormality with or without additional cytogenetic abnormalities

Dosing 10 mg once daily

WARNING • Embryo-fetal toxicity

• Hematologic toxicity

• Venous and arterial thromboembolism

Adverse Events • Most common (>15%): thrombocytopenia, neutropenia, diarrhea, pruritus,

rash, fatigue, constipation, nausea, nasopharyngitis, arthralgia, pyrexia, back pain, peripheral edema, cough, dizziness, headache, muscle cramp, dyspnea, pharyngitis, and epistaxis





Decitabine for injection3 Initial US approval: 2006

Indications and Usage in MDS Nucleoside metabolic inhibitor indicated for treatment of adult patients with MDS, including previously treated and untreated, de novo, and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk IPSS groups

Dosing • 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

• 5-d regimen: administer 20 mg/m2 continuous IV infusion over 1 h repeated daily for 5 d; repeat cycle every 4 wk

WARNING • Neutropenia and thrombocytopenia

• Embryo-fetal toxicity

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

Luspatercept-aamt for injection4 Initial US approval: 2019

Indications and Usage in MDS Luspatercept is an erythroid maturation agent indicated for the treatment of anemia failing an ESA and requiring 2 or more RBC units over 8 wk in adult patients with very low- to intermediate-risk MDS with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis

Limitations of use: not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia

Dosing • 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

WARNING • Thrombosis/thromboembolism: increased risk in patients with beta

thalassemia; monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly

• Hypertension: monitor BP during treatment; initiate anti-hypertensive treatment if necessary

• Embryo-fetal toxicity: may cause fetal harm; advise females of reproductive potential of the potential risk to a fetus and use of effective contraception

Adverse Events • Most common (>10%): fatigue, headache, musculoskeletal pain, arthralgia,

dizziness/vertigo, nausea, diarrhea, cough, abdominal pain, dyspnea, and hypersensitivity





ASTX727 (decitabine and cedazuridine) tablets5 Initial US approval: 2020

Indications and Usage in MDS Combination of decitabine (nucleoside metabolic inhibitor) and cedazuridine (cytidine deaminase inhibitor), indicated for treatment of adult patients with MDS, including previously treated and untreated, de novo, and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk IPSS groups

Dosing • Recommended dosage is 1 tablet (decitabine 35 mg and cedazuridine 100 mg)

taken orally once daily on d 1-5 of each 28-d cycle

• Take on an empty stomach

WARNING • Myelosuppression: Fatal and serious myelosuppression and infectious

complications can occur. Obtain complete blood cell counts prior to initiation, prior to each cycle, and as clinically indicated to monitor for response and toxicity. Delay the next cycle and resume at the same or reduced dose as recommended

• Embryo-fetal toxicity: can cause fetal harm; advise patients of reproductive potential of the potential risk to a fetus and use of effective contraception

Adverse Events • Most common (≥20%): fatigue, constipation, hemorrhage, myalgia, mucositis,

arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, decreased appetite, URTI, pneumonia, and transaminase increased

• Most common grade 3/4 laboratory abnormalities (≥50%): leukocytes decreased, platelet count decreased, neutrophil count decreased, and Hb decreased





NCT Number Study Title Conditions Interventions Status

NCT03173248Study of AG-120 (Ivosidenib) vs. Placebo in Combination With Azacitidine

in Patients With Previously Untreated Acute Myeloid Leukemia With an IDH1 Mutation (AGILE)

AML; newly diagnosed AML; untreated AML;

AML arising from MDS

AG-120 (ivosidenib) with azacitidine; placebo with

azacitidineRecruiting

NCT03682536

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

Myelodysplastic Syndromes (MDS) in ESA Naïve Subjects Who Require Red Blood Cell Transfusions (COMMANDS)

MDS Luspatercept; epoetin alfa Recruiting

NCT03745716 APR-246 & Azacitidine for the Treatment of TP53 Mutant Myelodysplastic Syndromes (MDS) MDS APR-246 + azacitidine;

azacitidineActive,

not recruiting

NCT02631070 A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes (MEDALIST) MDS Luspatercept; placebo

Active, not recruiting

Has results

NCT04256317 A Study of ASTX030 (Cedazuridine in Combination With Azacitidine) in MDS, CMML, or AML

MDS; CML; AML; MDS/neoplasm

Azacitidine; ASTX030 (cedazuridine +

azacitidine); cedazuridineRecruiting

NCT02907359 Guadecitabine (SGI-110) vs Treatment Choice in Adults With MDS or CMML Previously Treated With HMAs MDS; CMML Guadecitabine; treatment

choiceActive,

not recruiting

NCT01566695

The Efficacy and Safety of Oral Azacitidine Plus Best Supportive CareVersus Placebo and Best Supportive Care in Subjects With Red Blood

Cell (RBC) Transfusion-Dependent Anemia and Thrombocytopenia Due to International Prognostic Scoring System (IPSS) Low Risk Myelodysplastic

Syndrome (MDS)

MDS Oral azacitidine; placebo; best supportive care


Has results

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




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 (decitabine) 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.

NCT Number Study Title Conditions Interventions Status

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

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

placebo Recruiting

NCT03268954

Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS),

Chronic Myelomonocytic Leukemia (CMML), or Low-Blast Acute Myelogenous Leukemia (AML) (PANTHER)

MDS; CMML; AML Azacitidine; pevonedistat


NCT01243476 Study of REVLIMID (Lenalidomide) Versus Placebo in Patients With Low Risk Myelodysplastic Syndrome (SINTRA-REV) MDS Lenalidomide;

placeboActive,

not recruiting

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

azacitidine; placebo Recruiting

NCT04064060 A Study to Evaluate Long-term Safety in Subjects Who Have Participated in Other Luspatercept (ACE-536) Clinical Trials

MDS; beta thalassemia; MPN-associated

myelofibrosisLuspatercept Recruiting

NCT04401748

Safety And Efficacy Study Of Venetoclax Tablet With Intravenous or Subcutaneous Azacitidine to Assess Change in Complete Remission and Overall Survival In

Adult Participants With Newly Diagnosed Higher-Risk Myelodysplastic Syndrome (Verona)

MDS Venetoclax; azacitidine; placebo Recruiting

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


Documents

Diagnostic Criteria and Differential Diagnosis of MDS