Myelodysplastic Syndromes

1
Myelodysplastic Syndromes

• Nicole N. Balmer M.D.
• June 3rd, 2005

2
History of MDS

• First described in 1938 - 100 patients with
  refractory anemia were described Subsequently,
  the terms "preleukemic anemia and preleukemia
  were used.
• In 1963, a variant of acute leukemia was
  described, characterized by a prolonged and often
  benign clinical course, with a comparatively
  lower but variable percentage of bone marrow
  blasts the authors termed this condition
  "smoldering acute leukemia"

3
History of MDS

• In the 1970s, chronic myelomonocytic leukemia
  (CMML) was recognized as a unique preleukemic
  syndrome.
• In 1976, the French-American-British (FAB)
  Cooperative Group initially defined refractory
  anemia with excess blasts (RAEB) and CMML as
  preleukemic states. Six years later, the FAB
  group added three more categories to this
  classification scheme and adopted the present
  term "myelodysplastic syndromes".
• These disorders, and other members of the MDS
  "family were subsequently defined by the WHO.

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The Myelodyplastic Syndromes

• Six types of myelodysplastic syndromes according
  to WHO.
• Refractory anemia
• Refractory anemia with ringed sideroblasts
• Refractory cytopenia with multilineage dysplasia
• Refractory anemia with excess blasts
• Myelodysplastic syndrome, unclassifiable
• 5q- syndrome (myelodysplastic syndrome associated
  with isolated del (5q) chromosome abnormality
• Related syndromes
• Myelodysplastic/Myeloproliferative diseases

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Myelodysplastic Syndromes

• MDS Definition
• A group of disorders presenting with some
  evidence of bone marrow failure and dysplasia of
  one or more of the myeloid lineages, with lt20
  blasts in the blood or marrow.
• Epidemiology
• Occur primarily in older patients (most common gt
  70 years).

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MDS Clinical Symptoms

• Ecchymoses
• Fatigue
• Pallor
• Ecchymoses/petechiae
• Abnormal bleeding
• Infection

8
MDS Etiology

• Two etiologic categories of MDS
• 1.) De Novo
• Associated with
• -benzene exposure (gasoline)
• -cigarettesmoking
• -viruses -Fanconis
  anemia
• 2.) Therapy related
• Associated with
• -alkylating agent chemotherapy
• -radiation

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Prognostic Groups

• Two groups based on survival and evolution to
  acute leukemia
• 1.) Good group
• Refractory anemia (RA)
• Refractory anemia with ringed sideroblasts (RARS)
• 5q - syndrome
• 2.) Bad group
• Refractory anemia with excess blasts (RAEB)
• Refractory cytopenia with multilineage dysplasia
  (RCMD)
• MDS unclassified can be either

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Median Survival Myelodysplastic Syndromes
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Prognostic Scoring

• The International Myelodysplastic Syndrome
  Working Group developed a scoring system based on
  3 variables

0 0.5 1.0 1.5 2.0
Blasts lt5 5-10 -- 11-20 20-30
Karyotype Normal, -Y, del(5q), del(20q) Abnormal-ities NOS 3 abnormalities, chr 7 abnormalities
Cytopenia 0-1 2-3
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International Prognostic Scoring System Data
(IPSS)

• Overall median survival was 5.7, 3.5, 1.2, and
  0.4 years for patients with IPSS scores of zero
  (low risk), 0.5 to 1.0 (intermediate-1 risk), 1.5
  to 2.0 (intermediate-2 risk), and 2.5 to 3.5
  (high risk), respectively.    The time for 25
  percent of the patients in each of the four risk
  groups to evolve into acute leukemia was 9.4,
  3.3, 1.1, and 0.2 years, respectively.

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IPSS

• Other adverse prognostic factors which may
  improve the prognostic value of the IPSS include
•     -CD34 positivity of bone marrow nucleated
  cells    -Increased expression of the Wilms'
  tumor gene (WT1)  -Increased
  serum beta-2 microglobulin concentration  
•  -Mutations of the FLT3 gene
•  -Abnormal localization of immature
  precursors (ALIP).

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Refractory Anemia

• RA Definition
• Dyplasia of the erythroid series only.
• Clinically, anemia is refractory to hematinic
  therapy
• Myeloblasts lt 1 blood and lt 5 marrow
• lt15 ringed sideroblasts in marrow
• No Auer rods
• Other etiologies of erythroid abnormalities must
  be excluded. These include
• drug/toxin exposure -vitamin deficiency
• viral infection -congenital
  disease

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Refractory Anemia

• Epidemiology
• 5-10 of MDS cases.
• Older patients
• Morphology
• Anisopoikilocytosis on peripheral smears
• Dyserythropoiesis with nuclear abnormalities
  (megaloblastoid change)
• lt 15 ringed sideroblasts

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Refractory Anemia

• Genetics
• 25 may have genetic abnormalities
• Prognosis
• Median survival is 66 months
• 6 rate of progression to acute leukemia

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Peripheral Smear - Anisopoikilocytosis
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Dyserythropoeisis on Bone Marrow Aspirate
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Megaloblastoid Change on Bone Marrow Aspirate
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Refractory Anemia with Ringed Sideroblasts

• RARS definition
• Dyplasia of the erythroid series only.
• Clinically, anemia is refractory to hematinic
  therapy
• Myeloblasts lt 5 in marrow, absent in blood
• gt15 ringed sideroblasts in marrow
• No Auer rods
• Other etiologies of ringed sideroblasts must be
  excluded. These include
• Anti- tuberculosis drugs
• Alcoholism

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Refractory Anemia with Ringed Sideroblasts

• Epidemiology
• 10-12 of MDS cases.
• Older patients
• Males gt females
• Morphology
• Dimorphic pattern on peripheral smears
• Majority RBCs normochromic, 2nd population
  hypochromic
• Dyserythropoiesis with nuclear abnormalities
  (megaloblastoid change)

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Refractory Anemia with Ringed Sideroblasts

• Morphology (cont.)
• lt 15 ringed sideroblasts (RS)
• RS Erythroid precursor with 10 siderotic
  granules encircling 1/3 or more of the nucleus.
• If excess blasts present, this dictates
  diagnosis, despite percentage of RSs.

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Refractory Anemia with Ringed Sideroblasts

• Genetics
• Clonal chromosomal abnormalities in
• lt10 in fact, development of such an
  abnormality should prompt reassessment of
  diagnosis.
• Prognosis
• Median survival 6 years (72 months)
• 1-2 rate of progression to acute leukemia

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Dimorphic Red Cell Population
25
Ringed Sideroblasts
26
Ringed Sideroblasts
27
Megaloblastoid Change
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Refractory Cytopenia with Multilineage Dysplasia

• RCMD definition
• Dyplasia in 10 or more of cells in 2 or more
  myeloid lines.
• Myeloblasts lt 1 blasts in the blood and lt 5 in
  marrow.
• No Auer rods
• lt 1 x 109/L monocytes in blood

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Refractory Cytopenia with Multilineage Dysplasia

• Epidemiology
• 24 of MDS cases.
• Older patients
• Morphology
• Neutrophil abnormalities may include
• Hypogranulation
• Pseudo-Pelger-huet (hyposegmentation/barbells)
• Megkaryocyte abnormalities may include
• Hypolobation -Micromegakaryocytes

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Refractory Cytopenia with Multilineage Dysplasia

• Morphology (cont.)
• Erythroid abnormalities may include nuclear
  abnormalities such as
• megaloblastoid change -multilobation
• multinucleation
• In addition
• Erythroid presursors may be PAS positive
• If gt15 of erythroid precursors are ringed
  sideroblasts, call RCMD-RS

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Refractory Cytopenia with Multilineage Dysplasia

• Genetics
• Clonal chromosomal abnormalities found in up to
  50 of RCMD and RCMD-RS cases. The abnormalities
  include
• Trisomy 8 -del(7q)
  -del(5q)
• Monosomy 7 -Monosomy 5 -del(20q)
  
• Complex karyotypes
• Prognosis
• Median survival 33 months
• 11 rate of progression to acute leukemia
• RCMD and RCMD-RS similar survival
• Complex karyotypes worse survival (10-18
  months)

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Pelgeroid (pseudo Pelger-Huet) Neutrophil
33
Pelgeroid (pseudo Pelger-Huet) Neutrophil
34
Dyserythropoiesis on Bone Marrow Aspirate
35
Hypersegmented Neutrophil
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Micromegakaryocyte
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Refractory Anemia with Excess Blasts

• RAEB definition
• Refractory anemia with 5-19 myeloblasts in the
  bone marrow.
• RAEB-1
• 5-9 blasts in bone marrow and lt5 blasts in
  blood.
• RAEB-2
• 10-19 blasts in the bone marrow
• Auer rods present

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Refractory Anemia with Excess Blasts

• Epidemiology 40 of MDS cases.
• Older patients (over 50 years)
• Morphology
• Dysplasia of all three cell lines often present
• Neutrophil abnormalities may include
• Hypogranulation -hypersegmentation
• Pseudo-Pelger-huet (hyposegmentation/barbells)
• Pseudo Chediak-Higashi granules
• Megkaryocyte abnormalities may include
• Hypolobation -Micromegakaryocytes

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Refractory Anemia with Excess Blasts

• Morphology (cont.)
• Erythroid precursor abnormalities may include
• Abnormal lobulation -megaloblastoid change
• Multinucleation
• 0-19 myeloblasts in the blood
• 5-19 in the marrow
• Bone marrow
• Usually hypercellular (10-15 hypocellular)
• Abnormal localization of immature precursors
  (ALIP) may be present
• Immunophenotype
• Blasts express CD 13, CD33 or CD117
• The only MDS with a relevant phenotype

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Refractory Anemia with Excess Blasts

• Genetics
• Clonal chromosomal abnormalities found in 30 -
  50 of RAEB cases. The abnormalities include
• 8 -5 del(5q)
• -7 del(7q) Complex
  karyotypes
• Prognosis
• Median survival, RAEB-1 18 months
• Median survival, RAEB-2 10 months
• RAEB-1 25 rate of progression to acute
  leukemia
• RAEB-2 33 rate of progression to acute
  leukemia

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Hypercellular Bone Marrow
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Blasts and Hypogranulation
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Myeloblast with Auer Rod
44
Chediak-Higashi-like Granules

• Photograph courtesy of John Scariano, University
  of New Mexico, Dept. of Pathology

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Myelodysplastic Syndrome, Unclassifiable

• MDS-U definition
• Dysplasia of the neutrophil and/or megkaryocytic
  lines and no increased blasts
• Not otherwise classifiable as RA, RARS, RCMD and
  RAEB

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Myelodysplastic Syndrome, Unclassifiable

• Epidemiology
• Incidence unknown
• Older or younger persons
• Associated with a history of exposure to
  cytotoxic or radiation therapy
• Morphology
• BmBx usually hypercellular
• Dyplastic megakaryocytes may be prominent

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Myelodysplastic Syndrome, Unclassifiable

• Genetics
• May be normal, or clonal abnormalities the same
  as those found in other MDS syndromes.
• Prognosis
• Unknown
• Occasionally defining characteristics develop.
  Then case should be reclassified.

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Myelodysplastic Syndrome Associated With Isolated
del(5q) Chromosome Abnormality ( 5q- Syndrome)

• 5q- syndrome definition
• MDS with an isolated del(5q)
• lt5 blasts in blood and bone marrow
• Epidemiology
• Middle age to older women
• Clinical Presentation
• Refractory anemia, often severe
• Thrombocytosis may be present.

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Myelodysplastic Syndrome Associated with Isolated
del(5q) Chromosome Abnormality ( 5q- Syndrome)

• Morphology
• Peripheral Smear
• Marked macrocytic anemia.
• Slight leukopenia
• Normal to elevated platelets
• BmBx
• Erythroid dysplasia, varying degrees
• Small, hypolobated megakaryocytes
• Scattered aggregates of small lymphocytes

50
Myelodysplastic Syndrome Associated with Isolated
del(5q) Chromosome Abnormality ( 5q- Syndrome)

• Genetics
• Deletion between bands q31 and q 33 on chromosome
  5.
• Size of deletion and breakpoints are variable.
• Any additional cytogenetic abnormality excludes
  placement in this category.
• Prognosis
• Good long survival
• Those who develop more than 5 blasts may have
  shorter survival

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Hypolobated megakaryocytes
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Myelodysplastic/myeloproliferative diseases

• WHO category consists of 4 entities
• Chronic myelomonocytic leukemia (CMML)
• Formerly an MDS
• Atypical chronic myeloid leukemia (aCML)
• CML without BCR/ABL fusion gene
• Juvenile myelomonocytic leukemia (JMML)
• MDS/MPD-unclassified

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CMML Diagnostic Criteria
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MDS/MPD
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High vs. low intensity treatment

•  High intensity treatment requiring
  hospitalization, and included intensive
  combination chemotherapy and hematopoietic cell
  transplantation.    Low intensity
  outpatient-type treatments, such as use of
  hematopoietic growth factors, differentiation-indu
  cing agents, biologic response modifiers, and low
  intensity chemotherapy.

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MDS Treatment

•     Patients lt 60 years of age, who have good or
  excellent performance status and who are in the
  IPSS intermediate-2 or high risk categories
  (expected survival 0.3 to 1.8 years) high
  intensity therapies.    Patients lt 60 years of
  age, who have good or excellent performance
  status and who are in the low or intermediate-1
  category (expected survival 5 to 12 years) low
  intensity therapy or supportive care.  
   Patients gt60 years of age with good performance
  status and 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 gt60 years of
  age with good performance status and who are in
  the low or intermediate-1 category (expected
  survival 3 to 5 years) supportive care or low
  intensity therapy    

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Stem Cell Transplant

• HEMATOPOIETIC CELL TRANSPLANTATION Allogeneic HCT
  should be considered for patients with MDS who
  are under the age of 60 and who have an
  HLA-matched sibling donor.
• 60 and 40 chance of cure after allo-HCT in low
  and intermediate risk patients respectively
• Transplant-related mortality and the relapse rate
  at five years are as high as 40 percent.

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Azacitidine

• Azacitadine (Vidaza) the first approved treatment
  of MDS
• 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.
  (complete or partial normalization of blood in
  the bone marrow and normal levels of blood cells
  and need for blood transfusions was eliminated)
• Side effects nausea, anemia, low platelets in
  blood, diarrhea, fatigue, irritation at the
  injection site, and constipation.

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Revlimid

• Thalidomide derivative (revlimid) Revlimid is a
  thalidomide derivative without the neurologic
  toxicity of the parent compound. Used in MM and
  promising in MDS.
• Restoration of a normal karyotype was noted in 11
  of 17 informative patients.
• Erythroid response was highest in patients with
  Low/Int-1 IPSS scores (71 percent) and in those
  with the 5q- syndrome (91 percent).
• Dose-dependent myelosuppression was the most
  common adverse event.
• The results of multicenter phase II trials of
  this agent are awaited.

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Decitabine

• Decitabine Another pyrimidine nucleoside
  similar to 5-aza is 5-aza-2'-deoxycytidine (DAC,
  decitabine). Both agents strongly inhibit DNA
  methylation and are capable of inducing cell
  differentiation 86-88.
• 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
• High toxicity fever, infection, sepsis,
  neutropenia, anemia, and thrombocytopenia

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Hypocellular MDS Treatment

• Immunosuppressive drugs Patients with
  hypocellular MDS are believed to have
  immune-mediated hematopoietic suppression,
  perhaps due to the presence of an abnormal T cell
  response
• Some of these patients have responded to
  immunosuppressive therapies such as antithymocyte
  globulin (ATG)

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Future Therapies

• Valproic acid (VPA) has been shown to inhibit
  histone deacetylase activity and to synergize
  with all-trans retinoic acid (ATRA) in the
  differentiation induction of acute myelogenous
  leukemia (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.

63
References

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  Myelodysplastic syndromes Introduction. In
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• 2.)Wells, DA, Benesch, M, Loken, MR, et al.
  Myeloid and monocytic dyspoiesis as determined by
  flow cytometric scoring in myelodysplastic
  syndrome correlates with the IPSS and with
  outcome after hematopoietic stem cell
  transplantation. Blood 2003 102394.

64
References

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References

• 7.)Passmore, SJ, Chessells, JM, Kempski, H, et
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Acknowledgments

• Dr. John Ryder
• Dr. Bryan Abbott