Mds

Myelodysplastic Syndromes

by: amirhossein heydarian

outlines

Overview

presntation

Differential diagnosis

Workup

Treatment

Medication

Overview

Background:

The myelodysplastic syndromes (MDS) encompass a heterogeneous group of malignant bone marrow diseases characterized by ineffective, dysplastic hematopoiesis with subsequent pancytopenia, and an increased risk for developing AML.

Overview (Pathophysiology)

MDS develops when a clonal mutation predominates in the bone marrow, suppressing healthy stem cells.

MDS may result from:

Cytotoxic chemotherapy Radiation Viral infection Genotoxic chemicals (eg, benzene)

Overview (Etiology)

Two etiologic categories of MDS:

1.) De Novo:Associated with: -benzene exposure (gasoline) -cigarette smoking -viruses -Fanconi’s anemia

2.) Therapy related:Associated with: -alkylating agent chemotherapy

-radiation

Overview (Etiology) cont.

Cytogenetically, patients with MDS or AML fall into 3 groups:

Normal karyotype Balanced chromosomal abnormality causing the generation of fusion

oncogenes Complex karyotypes (usually >3 abnormalities)

Overview (Epidemiology)

Peak incidence: 60–90 years of age (Median age: 74 years)

3.6–12.6 per 100,000 cases

> 20 per 100,000 cases at 70 years of age

<10% are younger than 50 years.

Typical MDS patient Elderly Has shortened life expectancy, even with low-risk MDS ineffective

hemotopoiesis Male predominance

Overview (Epidemiology) cont.

Overview (Classification)

Myelodysplastic syndromes (MDS) were originally classified more than 20 years ago at an international conference.

This system was known as the French-American-British (FAB) classification.

The system used today is the World Health Organization (WHO) classification.

This system seems to be more helpful than the FAB classification in predicting prognosis.

Overview (Classification) cont.

The WHO system recognizes 7 types of MDS: Refractory cytopenia with unilineage dysplasia (RCUD) Refractory anemia with ringed sideroblasts (RARS) Refractory cytopenia with multilineage dysplasia (RCMD) Refractory anemia with excess blasts-1 (RAEB-1) Refractory anemia with excess blasts-2 (RAEB-2) Myelodysplastic syndrome, unclassified (MDS-U) Myelodysplastic syndrome associated with isolated del(5q)

Overview (Classification) cont.Refractory cytopenia with unilineage dysplasia (RCUD)

Blood findings:UnicytopeniaNo or rare blasts (<1%)

Bone marrow findings:Unilineage dysplasia ≥ 10% of the cells of the affected lineage are dysplastic<5% blasts<15% of the erythroid precursors are ring sideroblasts

Overview (Classification) cont.Refractory anemia with ringed sideroblasts (RARS)

Blood findings:

AnemiaNo blasts

Bone marrow findings:Erythroid dysplasia only≥ 15% of erythroid precursors are ring sideroblasts

Overview (Classification) cont.Refractory cytopenia with multilineage dysplasia (RCMD)

Blood findings:

Cytopenia(s)No or rare blasts (<1%)No Auer rods<1x109/l monocytes

Bone marrow findings:Dysplasia in ≥ 10% of cells in two or more myeloid lineages (neutrophil and/or

erythroid precursors and/or megakaryocytes)<5% blastsNo Auer rods±15% ring sideroblasts

Overview (Classification) cont.Refractory anemia with excess blasts-1 (RAEB-1)

Blood findings: Cytopenia(s) <5% blasts No Auer rods <1x109/l monocytes

Bone marrow findings:Unilineage or multilineage dysplasia5-9% blastsNo Auer rods

Overview (Classification) cont.Refractory anemia with excess blasts-2 (RAEB-2)

Blood findings:

Cytopenia(s)5-19% blastsAuer rods ±<1x109/l monocytes

Bone marrow findings:Unilineage or multilineage dysplasia10-19% blastsAuer rods±

Overview (Classification) cont.

Myelodysplastic syndrome, unclassified (MDS-U)

Blood findings:

Cytopenias≤ 1% blasts

Bone marrow findings:Unequivocal dysplasia in less than 10% of cells in one or more myeloid cell

lines<5% blasts

Overview (Classification) cont.Myelodysplastic syndrome associated with isolated del(5q)

Blood findings:AnaemiaUsually normal or increased platelet countNo or rare blasts (<1%)

Bone marrow findings:Normal to increased megakaryocytes with hypolobated nuclei<5% blastsIsolated del(5q) cytogenetic abnormalityNo auer rods

Overview (Prognosis)

MDS is a very heterogenous disease both from a pathogenetic, clinical and prognostic viewpoint.

IPSS is the most widely used prognostic model.

A total of 7012 patients from 5 different MDS databases formed the basis of the IPSS.

Overview (Prognosis) cont. IPSS (International Prognostic Scoring System) for

Myelodysplastic Syndromes

IPSS evaluates the prognosis at diagnosis and separates patients into 5 risk groups.

Cytogenetics, blast percentage and degree of cytopenias are the basis of the IPSS system.

IPSS prognostic groups and score values

IPSS prognostic groups and score values cont.

Ovweview (Additional prognostic factors)

Comorbidity:Cardiac, liver, renal, pulmonary disease and solid

tumors were found to independently affect the risk of non-leukemic death.

BM Fibrosis

Mutations: Point mutations in TP53, EZH2, ETV6, RUNX1, NRAS and ASXL1 have been associated with poor prognosis.

Ovweview ( Risk factors)

Heritable Age > 70 years Male gender Inherited congenital abnormalities

Fanconi anemia

Familial MDS Immune dysfunction DNA Repair Deficiencies

Acquired Chemotherapy Environmental/occupational Tobacco (Benzene) Ionizing radiation

outlines

Overview

presntation

Differential diagnosis

Workup

Treatment

Medication

Presntation (Symptoms) The development of myelodysplastic syndrome (MDS) may be preceded by a few

years by an unexplained macrocytic anemia with no evidence of megaloblastic anemia and a mild thrombocytopenia or neutropenia.

Symptoms such as:Fatigue and malaise result from anemiasymptoms of chronic heart failurePetechiae, ecchymoses, and nose and gum bleeding result from low platelet countFever, cough, dysuria, or shock may be manifestations of serious bacterial or

fungal infections associated with neutropenia

Presntation (Physical Examination) On physical examination, patients with myelodysplastic syndrome (MDS)

may have evidence of thrombocytopenia, anemia, and/or neutropenia.

Thrombocytopenia typically manifests as:

Petechiae, ecchymoses, epistaxis, gum bleeding, Hemoptysis, hematuria, and blood in stools may occur.

Anemia typically manifests as:

Pallor of the skin and mucosal membranes, fatigue, tachycardia, congestive heart failure may be manifestations of severe anemia.

The presence of fever and infections, such as pneumonias and urinary tract infections, may be due to the neutropenia associated with MDS.

outlines

Overview

presntation

Differential diagnosis

Workup

Treatment

Medication

Differential diagnosis

B12 / folate deficiencyRecent cytotoxic therapyHIV infectionAnemia of chronic disorders

(infection, inflammation, cancer)Autoimmune cytopeniaChronic liver disease Exposure to heavy metals

Hairy cell leukemiaFelty syndromeITPNeutropeniaExcessive alcohol intakePlatelet disordersPNH

outlines

Overview

presntation

Differential diagnosis

Workup

Treatment

Medication

Workup (Approach Considerations)

The workup in patients with possible MDS includes:

Patient historyCBC and DiffPeripheral blood smearBone marrow studies:

Cytogenetic Studies

Histologic Findings

Staging

Workup (Differential Diagnosis)

RBC-folate/S-folic acid Serum cobalamins Serum Iron, transferrin (TIBC) Ferritin, LDH Bilirubin Haptoglobin, DAT (Coombs test)

Albumin Uric acid Creatinine S-erythropoietin, S- protein electrophoresis Alkaline phosphatase

Workup (Staging)

IPSS Score for Staging MDS:

outlines

Overview

presntation

Differential diagnosis

Workup

Treatment

Medication

Treatment

range from ‘supportive’ to the ‘intensive’.

Patients < 60 years of age, who are in the low or intermediate-1 category

(expected survival 5 to 12 years) = low intensity therapy or supportive care.

Patients >60 years of age who are in the low or intermediate-1 category (expected survival 3 to 5 years) = supportive care or low intensity therapy.    

Treatment cont.

Patients >60 years of age who are in the IPSS intermediate-2 or high risk categories (expected survival 0.5 to 1.1 years) = low intensity therapy, although selected patients could be candidates for high intensity therapies.

Patients < 60 years of age, who are in the IPSS intermediate-2 or high risk categories (expected survival 0.3 to 1.8 years) = high intensity therapies.

Treatment (Supportive therapy)

Transfusion Red cell transfusions

Platelet transfusion

Iron Chelation more than 25 units of red cell transfusion Desferrioxamine (DFO)

Deferasirox

Deferiprone

Treatment (Supportive therapy)

Tranexamic acid For patients with low platelet count and bleeding tendency

Treatment and prevention of infections Routine use of prophylactic antibiotic treatment cannot be recommended, but may be

considered in patients with repeated infections.

G-CSF treatment

Erythropoietin

Treatment (intensive therapy)

Cytotoxic chemotherapy is used in patients with MDS with increasing myeloblasts and those who have progressed to acute leukemia.

The usual combination treatment is a cytarabine-anthracycline combination, which yields a response rate of 30-40% (high complication rate and morbidity in elderly patients).

Drugs such as 5-azacytidine (Vidaza), 5-aza-2-deoxycytidine (decitabine [Dacogen]), and lenalidomide (Revlimid) are now approved by FDA for MDS

Treatment (BMT) Bone marrow transplantation with a matched allogeneic or syngeneic

donor is used in patients with poor prognoses or late-stage MDS who are aged 55 years or younger and have an available donor.

Because most patients are elderly and only a few young patients MDS will have a matched donor, the use of bone marrow transplantation is limited.

The use of nonmyeloablative (mini) bone marrow transplantation and reduced-intensity conditioning regimens has been used in elderly patients as old as 75 years with some success.

Treatment (BMT)

Bone marrow transplant should be considered when ‘curative’ therapy is thought to be appropriate.

60 and 40% chance of cure after allo-HCT in low and intermediate risk patients.

outlines

Overview

presntation

Differential diagnosis

Workup

Treatment

Medications

Medications

Azacytidine

Azacitadine (Vidaza) the first approved treatment of MDS

Significant benefit to patients with aggressive MDS when treated with Azacytidine on clinical trials (USA and Europe)

Reduced red cell transfusion

Improvement in survival

Less chance of MDS deteriorating

Results not influenced by patient age, blast cells, karyotype

Medications

Azacytidine.. Drug administered by injection (but oral preparation in development)

Azacitidine is a member of a class of drugs in development known as "hypomethylating" or "demethylating" agents

About 15% of patients in the three trials had complete or partial responses to Vidaza.

Medications

Lenalidomide

Should be considered for 5q- syndrome

Oral medication

Eliminates need for transfusion in 67% of patients

Not yet licensed in Europe

Erythroid response was highest in patients with Low/Int-1 IPSS scores (71 percent) and in those with the 5q- syndrome (91 percent).

MedicationsDecitabine

strongly inhibit DNA methylation and are capable of

inducing cell differentiation.

25-61% resopnse rate

Major cytogenetic responses were noted in 31 percent of those with abnormal pretreatment cytogenetics and were associated with a reduced risk of death

Medications

Anti-thymocyte Globulin (ATG)

May be indicated in low-risk MDS

(with reduced bone marrow cells)

Improves blood counts in 30-50% of cases

Future TherapiesValproic acid (VPA)

has been shown to inhibit histone deacetylase activity and to

synergize with ATRA in the differentiation induction of AML

blasts in vitro.

Recent studies have found that VPA is of therapeutic benefit for patients with MDS, and ATRA may be effective when added later.

Thank you for your kind attention