Bone Marrow Failure Syndromes - PowerPoint Presentation

Slide1

Bone Marrow Failure Syndromes

Brian Boulmay

,

MD

Slide2

Bone Marrow Failure

Ineffective marrow-poeisis is the final endpoint of many diseases.

Congenital

Acquired

Genetic

Environmental or iatrogenic causes

Congenital marrow failure can present at any age.

Usually in childhood.

Some exceptions

Marrow failure often presents with single lineage declines

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Bone Marrow Failure

Early onset of marrow disorders can give a clue to genetic v. acquired syndromes

Dysmorphic body findings

Some may present later in life:

dyskeratosis congenita

Genetic testing will be confirmatory

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Inherited Syndromes

Inheritance patterns of inherited forms of marrow failure are variable:

X linked

Autosomal recessive

Autosomal dominant

Not every inherited syndrome has a clear genetic etiology

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Inherited Syndromes

Many of the inherited syndromes have an increased risk of acute leukemia and solid tumors.

Penetrance of a disorder may vary within a family.

Slide6

Marrow morphology

Examination of marrow morphology in a patient with single or multi-lineage cytopenias can be very non-specific.

Often just see decreased marrow elements

Clinical correlates and genetic/molecular analysis is key.

Slide7

Inherited/Constitutional Causes

Shwachman- Diamond Syndrome

Diamond- Blackfan Anemia

Dyskeratosis congenita

Fanconi Anemia

Down’s Syndrome

Familial HLH

Slide8

Shwachman-Diamond Syndrome

Autosomal recessive.

Mutation of

SBDS

gene on Chr 7.

The SBDS protein is involved with mitotic spindle stabilization

Causes a proliferative defect

Short, pancreatic exocrine deficiency,

neutropenia.

May have severe anemia, thrombocytopenia

Longterm increased risk of MDS/AML

Androgens, G-CSF are temporizing measure

SCT will correct the hematologic abnormality

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Diamond-Blackfan Syndrome

Autosomal dominantPure red cell aplasiaMutation of the RPS19 gene on Chr 19Plurality of patients, 25%Involved in ribosome assemblyConsiderable variation in presentation:Hydrops fetalispresentation in adulthoodPhysical phenotype: “tow-colored hair, snub nose, wide set eyes, intelligent expression”Web neck, short stature, triphalangeal thumb

Cathie

Arch Dis Chil

1950

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Diamond-Blackfan Syndrome

Marrow and peripheral blood triad:

Anemia

Reticulocytopenia

Absence of red cell precursors in the marrow

(Multilineage hypoplasia may develop in long term survivors)

Erythrocyte adenosine deaminase (ADA) levels high

Glucocorticosteroids are the classic therapy

Not effective in all. Adverse effects in children.

SCT the definitive therapy.

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Dyskeratosis congenita

X-linked, autosomal dominant or autosomal recessive.

Very rare

Mutations involve genes of telomere maintenance or the telomere complex*

DKC1- X linked

TERC- Dominant form

TERT

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Dyskeratosis congenita

Physical findings. The mucocutaneous triad:

Leukoplakia

Nail dystrophy

Reticulated skin hyperpigmentation

Can be subtle and only appear later in life.

Slide14

Dermopath.com, accessed 1/2014

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Dyskeratosis congenita

Typically starts with anemia, with high MCV and Hgb F and thrombocytopenia

Progresses to pancytopenia

Median age at presentation is 16 years old

Diagnosis made by

flow-FISH

of telomere length or

quant PCR of telomere DNA

or leukocytes

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Fanconi Anemia

Very rare (1:1,000,000 births)

Autosomal recessive inheritance

Due to mutation in the

FANC

gene

Protein products of this gene family protect against DNA cross linking.

Most patients present around 8 years old.

Can present in adulthood.

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Fanconi Anemia

60% of patients have a physical exam finding

Absent radius, absent thumb

Short

Microcephaly, hypertelorism

Skin pigment abnormalities (café au lait spots)

Confirmatory testing: lymphocyte chromosomal breakage on diepoxybutane exposure.

Differentiates from aplastic anemia

Slide18

Fanconi.co.za, accessed 12/2013

Slide19

Fanconi Anemia

Therapy:

Androgenic steroids

SCT

Risks:

Increased risk for solid tumors, MDS and AML

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Acquired single lineage marrow failure

Parvovirus B19

Thymoma associated pure red cell aplasia

Iron Deficiency

Anemia of chronic inflammation

Nutritional deficiencies

B12

Folate

Levamisole tainted cocaine

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Acquired multilineage marrow syndromes

Aplastic anemia (autoimmune)

Paroxysmal nocturnal hemoglobinuria

Myelodysplastic syndrome

HIV B12 def.

Hepatitis C Pregnancy

Bone marrow replacement SLE

Cancer

Myelofibrosis

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Aplastic anemia

Frequency 1:1,000,000

Occurs at any age

Progressive pancytopenia

Often presents with severe pancytopenia

Needs to be differentiated from FA or DC, even in adults.

Consider PNH in differential.

Rule out other marrow injuries

HIV

Hepatitis

Drugs/radiation

Sulfas, seizure meds, HIV meds

ETOH

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Aplastic Anemia

Cellularity <25% of normalMaturation usually normalRemnant cellularity usually lymphs, plasma cellsConsider hypocellular MDS or PNH

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Aplastic anemia

On marrow:

No fibrosis

No malignant cells

Hemapoietic precursors do not appear dysplastic

Cytogenetics should be normal

Slide25

Aplastic Anemia

A population of CD55- and CD59- cells may be found in patients with AAMaybe as high as 23% of lymphocytesDoes not mean patient has PNHDon’t treat as PNHPredicts response to ATG/CyA

Sugimori Blood 2006

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Aplastic Anemia

Classification:

Moderate aplastic anemia 

Bone marrow cellularity <30 percent

Absence of severe pancytopenia

Depression of at least two of three blood elements below normal

Severe aplastic anemia 

A bone marrow biopsy showing <25 percent of normal cellularity, 

or

A bone marrow biopsy showing <50 percent normal

fewer than 30 percent of the cells are hematopoietic and at least two of the following are present: absolute reticulocyte count <40,000/microliter; absolute neutrophil count (ANC) <500/microliter; or platelet count <20,000/microliter.

Very severe aplastic anemia 

Criteria for severe aplastic anemia are met and the ANC is <200 

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Aplastic Anemia

Therapy:Combination of ATG /MP/ CyA results in higher response rates than with ATG/ MP alone 70% v 41% at four monthsLifetime relapse rates ultimately the same in both arms.

Frickhofen

Blood

2003

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Aplastic Anemia

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Aplastic Anemia

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Aplastic Anemia

Horse ATG versus rabbit ATG:Primary study endpoint was hematologic response at 6 months:68% versus 38%3 year OS favored horse ATG96% versus 76%

Scheinberg NEJM 2011

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Aplastic Anemia

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Aplastic Anemia

CyA should be stopped at 6 months2 year taper after the usual 6 months can delay relapse, but does not appear to prevent it.

Young Abs 2406 ASH 2011

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Aplastic Anemia

Therapy guidelines:

<20 with an HLA matched donor: transplant

Cat 2C rec for MUD.

20- 50 with an HLA matched donor: transplant

>50: immunosuppression

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Aplastic Anemia

Role of mimeticsG-CSF and erythropoietin have no effect in AAEltrombopag (ELT) is a TPO mimetic:Triggers the mpl surface receptor.Approved for use in ITP24 patients treated with ELT with refractory AA40% response rateMpl mutation now implicated in some familial AA

Walne Hematologica 2011; Olnes NEJM 2012

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Paroxysmal nocturnal hemoglobinuria

Defect in the glycosylphophatidylinositol anchor on the cell membrane.

Loss of the anchor results in absence of GPI linked proteins.

GPI encoded on the PIG-A gene

CD55: decay accelerating factor

CD59: membrane inhibitor of reactive lysis

Slide36

PNH

Result of CD59 loss:

Sensitivity of red cells to complement mediated hemolysis

Hemolysis is intravascular

Positive DAT (C3d)

Negative indirect Coombs

Other symptoms:

Unprovoked clotting, clots in unusual places

Aplasia

Myelodysplasia

Slide37

PNH

Historically, diagnosed with the Ham test or sucrose lysis test

Now, flow cytometry of

RBC

or leukocytes evaluating

for absence of CD59 and CD55

PNH clones can be found in AA

Need to consider the clinical scenario

Slide38

PNH

28% survival at 25 yearsMedian survival 14 yearsRates:pancytopenia 15%myelodysplasia 5%thrombosis 28%

Hillman NEJM 1995: Socie Lancet 1996

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PNH

Therapeutic considerations:Eculizumab (TRIUMPH Trial): Binds C5 complement and inhibits terminal complement activationResults in no need for transfusionsDecreased hemolysis defined by decreased baseline LDH

Hillmen NEJM 2006

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PNH

Therapeutic considerations:SHEPERD StudySimilar results as TRIUMPH96% of patients free of thrombosis over one yearDecreased need for transfusions€300,000 per year

Brodsky Blood 2008

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PNH

Housekeeping:

Iron replacement

Folic acid

Prophylactic anti-coagulation:

Retrospective data suggests it is indicated

All therapy is supportive and does not impact the natural history of the underlying disorder.

Unless transplanted

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Myelodyplastic Syndromes

MDS is a group of diseases characterized by:1) Ineffective red cell production2) Risk of transformation to leukemia3) Disorder arises from transformed hematopoietic stem cell4) Lineage decrease resulting in one or more cytopeniasApproximately 10,000 cases diagnosed per year

Aul Br J Hema 1992

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Myelodysplastic Syndromes

Median age at diagnosis is greater than 65 with a male predominance.

Associated with:

Benzene

Trisomy 21

Fanconi Anemia

PNH

TERT/TERC mutations

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MDS- The CBC

Most all patients with MDS will have anemia.Classically macrocyticOnly 5% of patients with MDS will present with cytopenias WITHOUT anemia.Thrombocytosis can be present.5q- syndrome3q21q26 syndromeThrombocytopenia without anemia or other cytopeniasThink del(20q)

Koeffler 1980

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MDS- The Bone Marrow

Characteristic cytogenetic features: -7 or del 7q-5 or del 5qdel 13qdel 11qdel 12pdel 9qt(11;16)t(2;11)

No matter what the blast count:

t(8;21)

inv 16

t(15;17)

This is leukemia and needs to be treated as such

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MDS- What else could it be

Idiopathic cytopenia of undetermined significance:An isolated cytopenia with minimal dysplasia and no cytogenetic abnormalities.10% go onto acute leukemiaAML

Schroder Ann Onc 2010

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MDS- What else could it be

MDS/MPN- A disorder in which dysplasia and proliferation are present.

BCR/Abl negative CML: ‘atypical CML’

Often characterized by dysplasia in neutrophils

CMML: Overproduction of monocytes

Anemia, thrombocyopenia, splenomegaly

Does not, by definition, have BCR/Abl, PDFR alpha or beta rearrangements

Slide48

MDS- What else could it be

Aplastic Anemia:

Most patients with MDS have normo/ hypercellular marrow.

Hypocellular marrows with normal cytogenetics: think AA

MDS with hypocellularity: think therapy related MDS

Myelofibrosis:

Marrow fibrosis is common in MDS, sometimes appraching that of PMF

Hyperfibotic MDS: usually no splenomegaly

PMF: 50% will have JAK2 V617F mutation

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MDS- What else could it be

HIV-

Can be hypercellular, dysplastic, fibrotic

Improves long periods of time with good HIV control

Slide50

MDS Classification

World Health Organization Classification:

Refractory cytopenia with unilineage dysplasia <5%

RA with ringed sideroblasts <5%

Refractory cytopenias with multilineage dysplasia 70%

Refractory anemia with excess blasts 25%

5q- 5%

MDS, NOS 5%

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MDS Therapy

Most patients are palliative intent

Therapy is indicated if:

Symptomatic anemia

Symptomatic thrombocytopenia

Infection complications from neutropenia

Slide52

MDS Therapy

IPSS (old):

Percentage

of Bone Marrow Blasts

<5 percent (0 points)

5 to 10 percent (0.5 points)

11 to 20 percent (1.5 points)

21 to 30 percent (2.0 points)

Karyotype

Normal, Y-, 5q-, 20q- (0 points)

Abnormal chromosome 7 or 3 or more abnormalities (1.0 points)

All other cytogenic abnormalities (0.5 points)

Cytopenias (defined as hemoglobin <10, ANC<1800, platelet count <100K)

No cytopenia or cytopenia of 1 cell type (0 points)

Cytopenia of 2 or 3 cell types (0.5 points)

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MDS Therapy- The IPSS Score

0 Points:

Low (Median Survival of 5.7 yrs)

0.5-1 Points:

Intermediate 1 (Median Survival of 3.5 yrs.)

1.5-2.0 Points:

Intermediate 2 (Median Survival of 1.2 yrs.)

2.5-3.5 Points:

High (Median Survival of 0.4 yrs.)

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MDS Therapy

Options:

Hypomethylating agents

SCT

Best Supportive Care

Usually limited role for growth factors

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A word on the D-L Antibody

Paroxysmal cold hemoglobinuria

(

PCH):

rare

form of autoimmune hemolytic anemia

.

The

autoantibody that causes this syndrome is called the Donath Landsteiner

antibody

.

A

biphasic

cold

hemolysin:

Binds

to red blood

cells

at

cold temperatures and causes complement mediated

hemolysis

after

warming to body temperature

.

The

autoantibody often has specificity for the P blood group antigen.

The test:

Drawing

two tubes

of

blood:

One

is

incubated

at 37

o

 C for one hour

.

The other

tube

incubated

in an ice bath for 30 minutes and then transferred to a 37

o

 C water bath for an additional 30 minutes

.

Both

tubes

are

centrifuged:

If the serum of the tube incubated in the cold is hemoglobin-tinged and the serum of the tube that remained at 37

o

 C is clear, the patient has a Donath Landsteiner antibody

.