This document provides a history and overview of myelodysplastic syndromes (MDS). It describes how MDS was first characterized in the 1930s and named in the 1970s. It outlines the six main types of MDS according to the WHO classification system and related syndromes. It covers clinical features, etiology, prognostic scoring systems, characteristics of the main MDS subtypes, and treatment approaches for MDS.
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.
4.
5. 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
6. 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).
9. 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
10. Median Survival – Myelodysplastic
Syndromes
0
20
40
60
80
100
120
RA
EB-2
RA
EB-1
RCMD RC
MD-
RS
RA RARS 5q-
MDS Category
#
Months
11. 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,
del(5q),
del(20q)
Abnormal-
ities
NOS
≥ 3
abnormalities,
chr 7
abnormalities
Cytopenia
0-1 2-3
12. 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.
13. 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).
14. 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
16. Refractory Anemia
Genetics:
25% may have genetic abnormalities
Prognosis:
Median survival is 66 months
6% rate of progression to acute leukemia
20. 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
21. 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)
22. 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.
23. 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
28. 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
< 1 x 109
/L monocytes in blood
29. 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
30. 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
31. 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)
37. 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
38. 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
39. 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
40. 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
45. 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
46. 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
47. 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.
48. 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.
49. 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
55. 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.
56. 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
57. 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.
58. 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.
59. 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.
60. 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
61. 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)
62. 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.