THE DYSMYELOPOIETIC DISORDERS

INTRODUCTION

- 3 types of Clonal Proliferative disorder

1. Chronic Myeloproliferative Disorder (CMPD)- are condition in
which an abnormal pluripotential stem cell population arises in the bone
marrow.
2. Dysmyelopoietic Syndrome (DMPS)- a new pluripotential stem cell
line appear in the marrow.
- Peripheral cytopenias secondary to either an absolute
decrease in precursor cells in the marrow or ineffective cell
production
3. Acute Myeloid (Nonlymphocytic) Leukemia)- clonal proliferative
disorders of myeloid cell lines.
 HISTORY OF DISEASE DEFINITION

- Article by Block, Jacobson and Bethard in 1953

- “Preleukemic Acute Human Leukemia” – first cited the preleukemic disorders
- Dreyfus and Associates in 1972
- First describe among the group is (refractory Anemia with Excess myeloblast)
- Zittoun and Coworker in 1972
- Describe Chronic Myelomonocytic Leukemia
NOTE: Increase Marrow Blasts, the number of blast are not sufficient to make a
diagnosis of acute leukemia
- Saarni and Linman in 1973
- Introduced the concept of preleukemic syndrome
- Dyspoiesis of atleast two cell lines and blast must constitute less than 5% of the marrow cells
 FACTS ABOUT THE DISORDER!!

- More frequent in males than females

- Occur most frequently in patient 50 years or older but may be seen in any age group
- DMPS > ANLL

Causes of DMPS:
1. Secondary to X-ray therapy
2. Chemotherapy with alkylating agents
3. Toxic chemicals
4. Idiopathic or not known- referred to as “primary DMPS”
 PATHOPHYSIOLOGY

2 Hypotheses
1. DMPS growth of an abnormal clone of cells in the marrow (studies
shown that leukemic cells can suppress the growth of normal cell which
result to hypoplasia and pancytopenia)
2. Abnormal DMPS stem cell line has the ability to differentiate to mature
end stage cells that are abnormal in appearance and function.
(Dyserythropoiesis with ineffective erythropoiesis – ANEMIA WITH
ABNORMAL OVAL MACROCYTIC RED CELL)
 CLINICAL PRESENTATION

The Clinical Triad of Symptoms in Patient with DMPS

FATIGUE (pallor may be present to anemia)

FEVER (present of infection)

BLEEDING (petechiae or ecchymoses secondary to

thrombocytopenia)
 PERIPHERAL BLOOD AND BONE MARROW ABNORMALITIES

ERYTHROPOIESIS
- Hallmark of DMPS is dyserythropoiesis
- Abnormal maturation is megaloblastoid in type
signify the resemblance to the
megaloblastic maturation typical of vitamin B12
deficiency.

Characteristic: open chromatin pattern

attached to the nuclear membrane in large clumps.
Irregular nucleus. Hypochromic, microcytic in PB and in BM presence of
ringed sideroblast
 PERIPHERAL BLOOD AND BONE MARROW ABNORMALITIES

GRANULOPOIESIS
-dysgranulopoiesis is manifested of left shift with increase in myeloblast
+ Nuclear abnormalities- hyposegmentation (pelger-huet)
- hypersegmentation of neutrophil
+ Granular abnormalities- hypogranulation of neutrophil
- coarse abnormal granules (Pseudo-chediak-higashi)
Difficult to differentiate neutrophil and monocyte in which the neutrophil will
present a monocytoid features seen in Chronic Myelomonocytic Leukemia
 PERIPHERAL BLOOD AND BONE MARROW ABNORMALITIES

GRANULOPOIESIS
-French-American-British (FAB) classify DMPS into Type I and Type II blast
TYPE I Blast Type II Blast
Centrally located nucleus Centrally located nuclei
Fine chromatin pattern Slightly more mature chromatin
Prominent nucleolus Lower NC ratio
No cytoplasmic Granules Cytoplasm contains large granules one
Also referred to as abnormal progranulocyte (promyelocyte)

- Total combination of type 1 and 2 blast is used to calculate the percentage blasts.
- Tricot and Coworker reported abnormal localization of immature precursor (ALIP pattern)- prognostic
significance of survival and progression to acute leukemia
- GRANULOPOIESIS – localized in the bone trabeculae
- ERYTHROPOIESIS AND MEGAKARYOPOIESIS – centrally in the marrow space
- ALIP pattern clusters of blast appear in the central marrow
 PERIPHERAL BLOOD AND BONE MARROW ABNORMALITIES

MEGAKARYOCYTOPOIESIS
- Maturation arrest, with the majority of megakaryocyte being small to
medium size with a single or bilobed nucleus/
- Cytoplasm: may show vacuolization and lack of granulation
- Rare Cases(giant megakaryocyte with hypersegmentation of nucleus)
- Platelet may appear as swiss cheese appearance
 SPECIFIC CLINICOPATHOLOGIC FORMS OF
DYSMYELOPOIETIC SYNDROMES

FAB CLASSIFICATION OF DYSMYELOPOIETIC SYNDROME/

MYELODYSPLASTIC SYNDROMES

1. Refractory Anemia or Refractory Cytopenia (RA/RC)

2. Refractory Anemia with ringed sideroblast (RARS)
3. Refractory Anemia with Excess Blast (RAEB)
4. Chronic Myelomonocytic Leukemia (CMML)
5. Refractory Anemia with Excess Blast in Transformation (RAEBIT)
FAB CLASSIFICATION OF DYSMYELOPOIETIC SYNDROME/
MYELODYSPLASTIC SYNDROMES
REFRACTORY ANEMIA (RA/RC)

early dysplastic binucleated erythroid forms

• Bone marrow feature fibrosis is

not a feature of RA

dysplastic late erythroid precursors with irregular or lobated

nuclei
REFRACTORY ANEMIA WITH RINGED SIDEROBLAST (RARS)
(IDIOPATHIC ACQUIRED SIDEROBLASTIC ANEMIA)

• Similar to RA but the sine qua non is the presence of

pathologic ringed sideroblast
REFRACTORY ANEMIA WITH EXCESS BLAST (RAEB)

• May display any of the erythroid change of RA or RARS but may also have
dysgranulopoiesis and peripheral cytopenias of two cell lines
• Although RAEb is considered as DMPS, it has been found that when a child or young
adult presents with a morphologic picture of RAEB, the disease will be rapidly
progressive and should be classified as an M2 ANLL
CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML)

• According to Teereenhovi- pointed out

that RA, RARS and RAEB have transient
episode of PB monocytosis. Thus the
total wbc count is normal to low
• While in CMML- TOTAL WBC COUNT is
100 x 109/L
• Marrow shows striking granulocytic
hyperplasia with progression to mature
form
 CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML)

• FAB did not recognize that CMML might exist in a transition stage between
CMML and acute leukemia
• CMML increase of marrow blast to >20% before supervention of ANLL=
CMML in transformation
CMML in transformation- occur in infants or young children that resembles in
CMML seen in adults.
- deletion of Chromosome 7
- also called Ph1 –negative chronic granulocytic leukemia (CGL) or juvenile CGL
- myelomonocytic syndrome of infants/ monosomy 7 syndrome
REFRACTORY ANEMIA WITH EXCESS BLAST IN
TRANSFORMATION (RAEBIT)

• FAB criteria for RAEBIT

Bone marrow smears 1. 5%- more blast in PB
show increased proportion 2. >20% but <30% in the BM
of myeloblasts and a
trinucleated
3. Presence of Auer rods
micromegakaryocyte

binucleated
micromegakaryocyte 
 DYSMYELOPOIETIC DISORDERS NOT INCLUDED IN THE FAB
CLASSIFICATION

1. Refractory Cytopenia not meeting criteria for RA, RARS, RAEB or CMML
2. Secondary or Therapy related
3. Postleukemic
4. Single cell line Aplaisas
5. Paroxysmal Nocturnal Hemoglobinuria
6. RARS with Isodecentric X Abnormalities
7. Dyrsmegakaryocytopoiesis
1. With the 5q- Chromosome abnormalities
2. Without the 5q- chromosome abnormalities
8. Acute myelodysplasia with myelofibrosis
 Refractory Cytopenia not meeting criteria for RA,
RARS, RAEB or CMML

The majority of cases in peripheral

neutropenia or thrombocytopenia with
hyperplasia of the corresponding precursors
in the bone marrow and with maturation
arrest are immune or drug related
phenomenon.
 Secondary or Therapy Related Syndromes

Secondary DMPS usually follow the use of alkylator-type

chemotherapy agents either alone or in combination with
radiation therapy.
The delay between therapy and the onset of DMPS is usually
2-3 years but some 2 months.
Secondary DMPS begins as a refractory macrocytic anemia or
sideroblastic anemia.
 Postleukemic Syndrome

Foucar and Coworkers describe postleukemic

DMPS.
DMPS patient had progressed to overt ANLL
and after therapy, reverted to their
pretherapy DMPS status rather than to a
normal marrow or persistence of ANLL
 Single Cell Aplasias

Most cases of pure red cell aplasia represent

immune disorders of marrow or drugs such
as chloramphenicol. And there is some
studies that from pure red cell aplasia it
transfored into ANLL. In which there is only
one cell line is initially affected.
 Refractory Anemia with Ringed Sideroblasts and
Isodicentric X abnormality

Observed female patient with RARS with an

acquired isodicentric chromosomal abnormality
in whom the disorder rapidly transformed to
ANLL.
 Refractory Macrocytic Anemia with Megakaryocytic
Abnormalities (5q- Syndrome)
- 5q- Syndrome condition goes on to ANLL
- Disorder is both a cytogenetic and a clinicopathologic entity
- Deletion of the long arm of chromosome 5 between bands q15 and q31
- PB – refractory oval macrocytic anemia with normal or increased plateles
- BM- normocellular or hypercellular with megablastoid erythrocytic
hyperplasia.
 Dyspoietic Megakaryocytic Hyperplasia without 5q-
Chromosomal Abnormality or Marrow Fibrosis
Abrnomality
- Megakaryocytic hyperplasia and small mononuclear or bilobed
megakaryocytes but no 5q- chromosomal abnormality or marrow fibrosis
- Slightly dyspoiesis of both erythrocyte and granulocyctes