Myelodysplastic Syndromes

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					Myelodysplastic
 Syndromes
 Nicole N. Balmer M.D.
     June 3rd, 2005
               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"
                 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.
    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
    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 <20% blasts in the blood or
  marrow.
 Epidemiology:
 Occur primarily in older patients (most
  common > 70 years).
    MDS – Clinical Symptoms

 Ecchymoses
 Fatigue
 Pallor
 Ecchymoses/petechiae
 Abnormal bleeding
 Infection
               MDS Etiology
   Two etiologic categories of MDS:
1.) De Novo:
       Associated with:
         -benzene exposure (gasoline)
         -cigarettesmoking
         -viruses          -Fanconi’s anemia

2.) Therapy related:
       Associated with:
           -alkylating agent chemotherapy
           -radiation
               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
           Median Survival – Myelodysplastic
                     Syndromes
           120
           100
# Months




            80
            60
            40
            20
             0
                  RA     RA RCMD   RC    RA   RARS   5q-
                 EB-2   EB-1       MD-
                                   RS
                             MDS Category
                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
            <5          5-10               --        11-20   20-30
Karyotype Normal, -Y,   Abnormal-   ≥3
                                    abnormalities,
          del(5q),      ities       chr 7
          del(20q)      NOS         abnormalities



Cytopenia
            0-1         2-3
    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.
                         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).
             Refractory Anemia
   RA Definition:
   Dyplasia of the erythroid series only.
   Clinically, anemia is refractory to hematinic
    therapy
   Myeloblasts < 1% blood and < 5% marrow
   <15% 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
         Refractory Anemia
 Epidemiology:
 5-10% of MDS cases.
 Older patients
 Morphology:
 Anisopoikilocytosis on peripheral smears
 Dyserythropoiesis with nuclear
  abnormalities (megaloblastoid change)
 < 15% ringed sideroblasts
         Refractory Anemia
 Genetics:
 25% may have genetic abnormalities


 Prognosis:
 Median survival is 66 months
 6% rate of progression to acute leukemia
Peripheral Smear -
Anisopoikilocytosis
Dyserythropoeisis on Bone Marrow
            Aspirate
Megaloblastoid Change on Bone
       Marrow Aspirate
     Refractory Anemia with Ringed
              Sideroblasts
   RARS definition:
   Dyplasia of the erythroid series only.
   Clinically, anemia is refractory to hematinic
    therapy
   Myeloblasts < 5% in marrow, absent in blood
   >15% ringed sideroblasts in marrow
   No Auer rods
   Other etiologies of ringed sideroblasts must be
    excluded. These include:
    – Anti- tuberculosis drugs
    – Alcoholism
     Refractory Anemia with Ringed
              Sideroblasts
   Epidemiology:
   10-12% of MDS cases.
   Older patients
   Males > females
   Morphology:
   Dimorphic pattern on peripheral smears
    – Majority RBC’s normochromic, 2nd population
      hypochromic
   Dyserythropoiesis with nuclear abnormalities
    (megaloblastoid change)
    Refractory Anemia with Ringed
             Sideroblasts

 Morphology (con’t.)
 < 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 RS’s.
     Refractory Anemia with Ringed
              Sideroblasts
   Genetics:
   Clonal chromosomal abnormalities in
    <10%; 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
Dimorphic Red Cell Population
Ringed Sideroblasts
Ringed Sideroblasts
Megaloblastoid Change
      Refractory Cytopenia with
       Multilineage Dysplasia
 RCMD definition:
 Dyplasia in 10% or more of cells in 2 or
  more myeloid lines.
 Myeloblasts < 1% blasts in the blood and
  < 5% in marrow.
 No Auer rods
          9
 < 1 x 10 /L monocytes in blood
        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
       Refractory Cytopenia with
        Multilineage Dysplasia
 Morphology (con’t.)
 Erythroid abnormalities may include
  nuclear abnormalities such as:
    – megaloblastoid change       -multilobation
    – multinucleation
    – In addition:
       Erythroid presursors may be PAS positive
       If >15% of erythroid precursors are ringed
        sideroblasts, call = RCMD-RS
         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)
Pelgeroid (pseudo Pelger-Huet)
           Neutrophil
Pelgeroid (pseudo Pelger-Huet)
           Neutrophil
Dyserythropoiesis on Bone Marrow
            Aspirate
Hypersegmented Neutrophil
Micromegakaryocyte
    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 <5% blasts in
       blood.
    – RAEB-2:
       10-19% blasts in the bone marrow
       Auer rods present
     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
     Refractory Anemia with Excess
                 Blasts
   Morphology (con’t.)
   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
     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
Hypercellular Bone Marrow
Blasts and Hypogranulation
Myeloblast with Auer Rod
       Chediak-Higashi-like Granules




   Photograph courtesy of John Scariano, University of New Mexico, Dept. of Pathology
     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
      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
      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.
 Myelodysplastic Syndrome Associated With
 Isolated del(5q) Chromosome Abnormality
               ( 5q- Syndrome)
 5q- syndrome definition:
 MDS with an isolated del(5q)
 <5% blasts in blood and bone marrow

   Epidemiology:
   Middle age to older women

   Clinical Presentation:
   Refractory anemia, often severe
   Thrombocytosis may be present.
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
 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
Hypolobated megakaryocytes
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
CMML Diagnostic Criteria
MDS/MPD
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-inducing agents, biologic
    response modifiers, and low intensity
    chemotherapy.
                     MDS Treatment
      Patients < 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 < 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 >60 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 >60 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
           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.
                            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.
                         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.
                 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
    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)
           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.
                   References
 1.)Brunning, RD, Bennett, JM, Flandrin, G, et al.
  Myelodysplastic syndromes: Introduction. In Jaffe, ES,
  Harris, NL, Stein, H, Vardiman, JW, editors. World Health
  Organization Classification of Tumours. Pathology and
  Genetics of Tumours of Haematopoietic and Lymphoid
  Tissues. IARC Press: Lyon 2001.
 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; 102:394.
                     References

   3.)Seo, IS, Li, CY, Yam, LT. Myelodysplastic syndrome:
    Diagnostic implications of cytochemical and
    immunocytochemical studies. Mayo Clin Proc 1993;
    68:47.
   4.)So, CC, Wong, KF. Valproate-associated
    dysmyelopoiesis in elderly patients. Am J Clin Pathol
    2002; 118:225.
   5.)Ooi, J, Iseki, T, Takahashi, S, et al. Unrelated cord
    blood transplantation for adult patients with advanced
    myelodysplastic syndrome. Blood 2003; 101:4711.
   6.) Albitar, M, Manshouri, T, Shen, Y, et al.
    Myelodysplastic syndrome is not merely "preleukemia".
    Blood 2002; 100:791.
                     References

   7.)Passmore, SJ, Chessells, JM, Kempski, H, et al.
    Paediatric myelodysplastic syndromes and juvenile
    myelomonocytic leukaemia in the UK: a population-
    based study of incidence and survival. Br J Haematol
    2003; 121:758
   8.)Cheson, BD, Zwiebel, JA, Dancey, J, Murgo, A. Novel
    therapeutic agents for the treatment of myelodysplastic
    syndromes. Semin Oncol 2000; 27:560.
   9.)Estey E, Schrier S. Treatment and prognosis of mds
    www.uptodate.com, 2005.
   10.)Coll DC, Landaw, SA Clnical manifestations and
    diagnosis of the myelodysplastic syndromes. Blood.
    2004, 1;104(5):1266-9.
Acknowledgments


   Dr. John Ryder
  Dr. Bryan Abbott

				
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