Myelodysplasia Update

Andrea M. Sheehan, MD Associate Professor of Pathology & Immunology

Director of Hematopathology

August 7, 2014

Myelodysplastic Syndromes: Ineffective Hematopoiesis

Marrow looks like this: PB looks like this:

Hypercellular marrow Pancytopenia

General Features

Heterogenous group of disorders Present with some element of bone marrow

failure, ineffective hematopoiesis Dysplasia in one or more cell lines Blasts <20% Variable propensity for transformation to AML Mortality related to marrow failure or AML May arise de novo or be therapy related Usually an adult disease, but rarely seen in kids

May be associated with congenital marrow failure disorders or other syndromes

General Features

Can be difficult to diagnose

Morphologic dysplasia can be seen with reactive conditions

Viruses, drugs, toxic exposures, nutritional deficiencies, autoimmune disorders, post transplant, hemolytic anemias, etc.

Poorly prepared or stained smear can give you “dysplasia”

May have MDS without much morphologic dysplasia

Clonal cytogenetic abnormality is helpful if present

May have to make the diagnosis clinically after exclusion of other reactive causes for cytopenias

General Features

No single “MDS test” exists, clinical-lab-pathologic-cytogenetic correlation is essential

Classification & majority of literature based on adult patients – may not apply well to kids

Pediatric literature is messy Overlap with aplastic anemia

Many low grade pediatric MDS cases have hypocellular marrows

JMML often mixed in with old case series – now considered separate class of entities (myelodysplastic/ myeloproliferative neoplasms)

Pathologic Criteria for Dysplasia

Morphologic

>= 10% of the cells in a lineage

Some would argue 20% is a better cutoff for pediatrics

Cytogenetic abnormalities

Specific list of abnormalities

Alone & without morphologic dysplasia – considered presumptive evidence of MDS

Same list is used to define AML with myelodysplasia related changes

Cytogenetic Abnormalities Associated with MDS

Unbalanced

-7 or del(7q)

-5 or del(5q)

i(17q) or t(17p)

-13 or del(13q)

del(11q)

del(12p) or t(12p)

del(9q)

idic(X)(q13)

Balanced

t(11;16)(q23;p13.3)

t(3;21)(q26.2;q22.1)

t(1;3)(p36.3;q21/2)

t(2;11)(p21;q23)

inv(3)(q21q26.2)

t(6;9)(p23;q34)

+8, del(20q), -Y also associated with MDS but not enough by themselves to call MDS)

Morphologic Dysplasia

Sometimes in the eye of the beholder

Requires an adequate, well prepared, well stained bone marrow aspirate smear

Combination of nuclear and cytoplasmic features

Peripheral blood morphology also helpful

Abnormal neutrophils, red cells, platelets

Features of Dysplasia

Nuclear and cytoplasmic changes

Nuclear

Abnormal contours

Abnormal lobation

Cytoplasmic

Abnormal granulation

Auer rods

Too many blasts

Dysplastic Morphology: RBC’s

Megaloblastoid changes – nuclear/cytoplasmic dyssynchrony

Nuclear budding

Nuclear irregularity

Nuclear bridging

Poor hemoglobinization

Erythroid Dysplasia

Dimorphic RBCs

Ringed Sideroblasts

Dysplastic Morphology: Granulocytes

Hypogranularity “ghost cells”

Uncommonly hypergranular

Nuclear megaloblastoid changes Giant bands,

metamyelocytes

Segmentation abnormalities Usually hyposegmented

“pseudo Pelger Huet”

Dysplastic Morphology: Megs

Nuclear hyperchromasia

Separation of nuclear lobes

Hypolobation

“disappearing megakaryocyte syndrome”

They get small and hypolobated & so hard to spot on biopsy sections

CD61 or CD41 on a biopsy may help to pull them out

Micromegakaryocytes

Dysplastic Megakaryocytes

Micromegakaryocyte

Copyright ©2001 American Society of Hematology. Copyright restrictions may apply.

Vardiman, J. W ASH Image Bank 2001;2001:100197

Figure 8. This figure summarizes the characteristic findings associated with MDS with an isolated del(5q) syndrome

Once We Decide it IS MDS . . .

Classify it!

Blood and bone marrow findings are considered

Blood

Number of cytopenias

% circulating blasts

Presence or absence of Auer rods

Absence of monocytosis

Bone Marrow

Number of lineages with dysplasia

Presence or absence of ringed sideroblasts

Presence or absence of Auer rods

% blasts

Cytogenetic abnormality (presence/absence & type)

The Players (WHO 2008)

De novo Refractory cytopenia with unilineage dysplasia

Refractory anemia with ringed sideroblasts

Refractory cytopenias with multilineage dysplasia

Refractory anemia with excess blasts (I & II)

MDS with isolated 5q- (5q minus syndrome)

MDS, unclassified

Childhood MDS (refractory cytopenia of childhood)

Therapy related myeloid neoplasms MDS or AML

Previous history of chemotherapy +/- radiation

Myeloid leukemia associated with Down syndrome Includes MDS & AML (acute megakaryoblastic leukemia)

Disease Blood Marrow

RCUD Unicytopenia or bicytopenia; <1% blasts

Unilineage dysplasia (>10% cells in a lineage); <5% blasts, <15% ringed sideroblasts

RARS Anemia; no blasts >15% ringed sideroblasts; erythroid dysplasia only; <5% blasts

RCMD Cytopenias, <1% blasts, No Auer rods, <1x109/L monocytes

Dysplasia(>10% cells) in >= 2 lineages; <5% blasts; No Auer rods; +/- 15% ringed sideroblasts

RAEB-1 Cytopenia(s); <5% blasts; No Auer rods; <1x109/L monocytes

Unilineage or multilineage dysplasia; 5-9% blasts; No Auer rods

RAEB-2 Cytopenia(s); 5-19% blasts; +/- Auer rods; <1x109/L monocytes

Unilineage or multilineage dysplasia; 10-19% blasts; +/- Auer rods

Criteria for Classification (de novo)

Criteria Continued (de novo)

Disease Blood Marrow

MDS-U Cytopenias; <=1% blasts Unequivocal dysplasia (>10% cells) one or more cell lines; cytogenetic abnormality on list of presumptive MDS abnormalities; <5% blasts

5q- syndrome Anemia; normal or high platelets; No or <1% blasts

Normal or increased megakaryocytes with hypolobated nuclei; <5% blasts; isolated 5q-; no Auer rods

Blasts with Auer Rods

Will push to RAEB-II, regardless of blast count

Myeloid Leukemia Associated with Down Syndrome

Encompasses both MDS and AML (usually megakaryoblastic)

Pre-leukemic phase may last months, has features of RCC Morphologic dyplasia may be more

prominent than de novo RCC

No specific special diagnostic criteria, must meet other MDS or AML criteria

Childhood MDS

<5% of hematopoietic neoplasms in kids <14 years old

As in adults, may be primary (de novo) or secondary Secondary cases associated with:

Congenital or acquired bone marrow failure syndromes

Previous chemotherapy or radiation (therapy related)

RCC applies only to de novo MDS

Kids can get the same “high grade” MDS that adults can get Refractory anemia with excess blasts

Childhood MDS

Unlike adults, some types of low grade MDS are almost never seen in kids Refractory anemia

Refractory anemia with ringed sideroblasts

5q minus syndrome

Classification for “adult” low grade MDS does not apply well to kids Kids with low grade MDS usually have neutropenia or

thrombocytopenia rather than anemia

New entity of refractory cytopenia of childhood created to give kids a low-grade MDS category of their own

Traditionally part of pedi MDS, but not really now

Survival in Pediatric MDS

The IPSS scoring system for adult MDS does not work well in kids to stratify patients

Survival in Pediatric MDS

The IPSS scoring system for adult MDS does not work well in kids to stratify patients

Survival in Pediatric MDS

Blasts >= 5% or <5%

Platelets >= 100 or <100

An Illustrative Case

15 year old boy presents with chronic thrombocytopenia

Cytogenetics

45,XX, -7 [20]

FISH -7 in 84.5% of cells

Final Diagnosis

Myelodysplastic syndrome (Refractory cytopenia of

childhood)

RCC - Definition

Persistent cytopenia with <5% blasts in bone marrow

<2% blasts in peripheral blood

If blasts more than that, classify as refractory anemia with excess blasts!

No Auer rods Dysplastic changes in 2 cell lineages in the bone

marrow OR >10% dysplastic cells in a single lineage

Refractory Cytopenia of Childhood

Exclude other causes of morphologic dysplasia

75% of cases have hypocellular marrow May be hard to find the dysplastic cells and

distinguish from aplastic anemia

5-10% of age matched controls

RCC: Epidemiology & Clinical Features

50% of childhood MDS

Affects all age groups

Equal gender distribution

Patients present with symptoms of cytopenias 75% with thrombocytopenia (plt <150K)

50% with anemia (Hgb <10 g/dL) & macrocytic

WBC often decreased, 25% with severe neutropenia

Up to 20% may be asymptomatic

RCC – Differential Diagnosis

Morphologic dysplasia is NOT diagnostic of MDS!

Can also be seen in: Viral & other infections Nutritional deficiencies Metabolic diseases Drug or toxin effects Rheumatologic disorders, ALPS, mitochondrial

deletions

Also consider PNH, aplastic anemia during hematological recovery, inherited bone marrow failure syndromes

RCC

AA

RCC - Immunophenotype

CD41 or CD61 may help pull out the small dysplastic micromegakaryocytes

CD34 & CD117 should NOT show increased blasts

CD61 – dypslastic megs

RCC - Genetics

Most will have normal karyotype

Monosomy 7 most common genetic abnormality

Others may be seen (+8, complex)

RCC – Prognosis & Treatment

Karyotype is most important indicator

If monosomy 7, significantly high probability of progression

Normal or +8 generally stable course

Bone marrow transplant only curative regimen Treatment of choice for –7 or complex

Some patients may respond to immunosuppression as T cell suppression of hematopoiesis may be a factor in some cases with stable disease

Refractory Anemia w/ Excess Blasts

The other major type of MDS seen in kids

Patients usually present with BM failure

5-19% blasts in the bone marrow

Split into RAEB-1 & -2 based on blast count RAEB-1 = 5-9% in BM & <5% in PB

RAEB-2 = 10-19% in BM &/or 5-19% in PB &/or Auer rods are present

RAEB-T (20-29% blasts) may behave more like MDS than AML, so unless clinically acting like AML, should be considered MDS

RAEB

Usually dysplastic changes in all 3 cell lines, may be marked

Too many blasts, but less than 20% (or 30%) in PB & BM

Sometimes dysplasia is not prominent, but there are just too many blasts

Usually hypercellular marrow 10-15% with hypocellular marrow

May see ALIP (abnormal localization of immature precursors) Clusters of blasts located away from bony trabeculae

RAEB

30-50% with clonal cytogenetic abnormalities

+8, -5, del(5q), -7, del(7q), del(20q), complex

Blasts are usually myeloid

CD13+, CD33+, CD117+

Patients have progressive marrow failure, increasing cytopenias

25% of RAEB-1, 33% of RAEB-2 go to AML

Median survival 18mo RAEB-1, 10mo RAEB-2

May have better survival in children than adults

Another Case

8 year old girl

8 months off therapy for B-ALL

Now presents with persistent cytopenias

CD61

CD34

CD117

PAX-5

TdT

PBS

PBS

Additional Studies

Flow cytometry

4.8% myeloid blasts that express:

CD45 (dim), CD13, CD33, CD34, CD117, HLA-DR

Cytogenetics

Complex numerical and structural alterations including 5q31 deletion and monosomy 7

Diagnosis

Therapy related myeloid neoplasm (myelodysplastic syndrome)

Therapy Related Myeloid Neoplasms

Encompass MDS and AML

History of prior chemotherapy or radiation for some other neoplastic or non neoplastic disorder Also rarely seen post BMT

10-20% of pediatric MDS, AML, or MDS/MPN

Most commonly seen after treatment for Hodgkin’s, ALL, osteosarcoma, NHL, and Ewing’s We have seen a few cases after neuroblastoma,

ALL or Hodgkin’s therapy

Therapy Related Myeloid Neoplasms

After alkylating agents, increasing incidence with age

After topoisomerase II inhibitors, same across ages

Pathogenesis likely combination of genetic and environmental factors Patients with DNA repair disorders are at

increased risk (Fanconi anemia, Bloom syndrome, Down’s)

Genetic polymorphisms in drug metabolizing enzymes (such as glutathione S-transferase) likely also play a role

T-MDS/AML

Clinically present 1-10 years after primary tumor treatment Shorter latency for topo II related diseases (1-

5 years) then alkylating agent related (5-7 years)

May present with MDS, MDS progressing to AML or frank AML or MDS/MPN

Cytogenetic abnormalities common Alkylating agent related – losses of 5, 7

Topo II inhibitors – translocations (MLL)

5 & 7

MLL

Cytogenetics in Pediatric t-MDS

T-MDS/AML

Morphology not specific, follows criteria for de novo MDS, AML, or MDS/MPN

In general, a dismal prognosis 10-20% long term survival

Prognosis not related to blast count, MDS vs AML diagnosis, or other features other than cytogenetics

Abnormalities of 5 &/or 7 and complex karyotype have worst outcome

May have more favorable outcome with intensive chemotherapy with HSCT, if can achieve remission

Survival in Children with MDS (Primary vs therapy related)

Primary

Therapy related

Geez, Mom! You’re ending there? That’s

such a downer!!

Here’s a happier thought!

It’s time for lunch!

The mountains are waiting – time to explore!!