8/29/2013

1

Aplastic Anemia:

Current Thinking on the Disease,

Diagnosis and Non-Transplant

Treatment

Akiko Shimamura MD PhD

Fred Hutchinson Cancer Research Center

Seattle Children’s Hospital

University of Washington

AA&MDS International Foundation

September 7, 2013

Overview

• What is aplastic anemia?

• Causes of aplastic anemia

• Important lab tests

• Non-transplant treatment options

• Supportive care options healthy bone marrow Aplastic anemia

Images courtesy of Dr. Min Xu, Dept of PathologySeattle Children’s Hospital, Seattle, WA

Neutrophils

• Also called: granulocyte, “poly”, PMN, “seg”

• Function: Fights infection (bacteria and fungus) by engulfing/eating them

• ANC: Absolute Neutrophil Count– White blood cell count (WBC) X % neutrophils

Neutrophils

• “neutropenia”: ANC <1,500

• Generally do not start to see increased infection risk until ANC falls below 1,000

• Generally, the lower the ANC, the higher the potential risk of infection.

• Mild: 500-1000

• Moderate: 200-500

• Severe: <200

8/29/2013

2

Platelets

• Function: Help the blood to clot

Platelets

• Thrombocytopenia: platelet count <150,000

• Bleeding risk generally starts to increase when platelet counts fall below 100,000.

Bleeding risk

100,000-50,000: Mildly increased

50,000-20,000: Moderately increased

<10,000-20,000 Significantly increased

• Need to assess bleeding risk within clinical context (eg: surgery, risk of trauma, location of bleed)

• Function: Carry oxygen from the lungs to other organs/tissues

• “Hematocrit” and “Hemoglobin” provide a measure of the red blood cells. Normal levels vary with age and gender.

• “Reticulocytes” are young, newly produced red blood cells.

Red blood cells Aplastic anemia

Primary marrowdisease

Secondary- infection

-medications

-toxins-other disease

Acquired-autoimmune

-idiopathic

-post-hepatitis

Inherited-Fanconi anemia

-Dyskeratosis congenita

-Shwachman-Diamond syndrome-Amegakaryocytic thrombocytopenia

-Diamond-Blackfan anemia

-GATA-2

Severe Aplastic Anemia

(Camitta criteria)

• Two of the following:

– ANC<500 (<200=“very severe”)

– Platelets <20,000

– Low reticulocyte count (corrected for hemoglobin)

• Marrow cellularity <25%

• Moderate aplastic anemia: variable

definitions

Laboratory tests

• Complete blood count (CBC) with

differential

• Bone marrow biopsy

– Cellularity

• Bone marrow aspirate

– Morphology

– ?culture

– Cytogenetics

8/29/2013

3

Cytogenetic clones

x

x

x

x

x

x

x

x

x

x

x

Cytogenetics

Monosomy 7 Fluorescent in-situ

hybridization (FISH)

Normal (2 copies) Abnormal (one copy)

Paroxysmal nocturnal

hemoglobinuria (PNH)

• Clinical features:

– hemolytic anemia (red blood cell

destruction -> anemia)

– thrombosis (blood clots)

– aplastic anemia

PNH (cont)

• GPI anchors other proteins to the cell surface

• PNH cells are deficient in all GPI-anchored

cell surface proteins (eg: CD59 and CD55,

which protect cells from complement)

CD59G

P

I

G

P

I

CD55

8/29/2013

4

PNH

• Small clone size typically asymptomatic

• Unclear whether presence of small PNH

clone affects outcomes

• Treatment approach for AA with

asymptomatic PNH clone is generally the

same

+ DEB or MMC

Courtesy of Lisa Moreau, Dana Farber Cancer Institute, Boston, MA

Fanconi Anemia: Diagnostic Testing

Diagnostic Workup

• Why should we test for inherited bone marrow failure syndromes?

– Poor response to ATG/Cyclosporine (CyA)

– Standard transplant regimens may be highly toxic � Require reduced intensity conditioning regimen

– Inform donor choice

– Family counseling (eg: cord blood banking)

Diagnostic Workup

• Look for clues to inherited bone marrow failure syndrome:

– Clinical history

– Family history

• Low blood counts, malignancies at a young age, excessive toxicity with chemo/radiation, physical disorders

– Physical exam

• Shimamura and Alter, Blood Reviews, 2010. 24(3): 101-122.

Laboratory tests

• Paroxysmal nocturnal hemoglobinuria

• Fanconi anemia (children, young adults)

• AST, ALT, GGT, bilirubin (liver)

• BUN, creatinine, electrolytes (kidney)

• Tests for infections

• Tests for immune/rheumatologic

disorders

• HLA testing of patient and siblings

• Telomere length testing?

TTAGGG n

AATCCC n

5’3’

X-linke

dominant

dominant &

recessive

recessive

DKC1TERC

TERT NOP10

NHP2

TIN2

TIN2

TIN2

TIN2

T

dominantShelterin

Slide courtesy of Dr. Blanche AlterAnd Dr. Sharon Savage, NCI.Published in Shimamura and Alter, Blood Reviews, 2010. Vol 24: pp 101-122

Telomeres

8/29/2013

5

Telomeres shorten with age Telomere length and AA

• Very short telomeres are associated

with an inherited bone marrow failure syndrome (dyskeratosis congenita)

• Shorter telomere length:

– Decreased response to ATG/CyA

– Increased risk of relapse

– Increased risk of clonal progression (MDS)

Scheinberg et al. JAMA 2010; 304: 1358-1364

When to treat?

• Severe or very severe aplastic anemia

• Transfusion-dependent cytopenias

• Note: Limited data on whether it is

advantageous to treat patients with moderate

AA. Some are stable and some improve

spontaneously. Generally work up and

observe.

BMT vs ATG/CsA?

• Survival

• Short-term versus long-term complications

• BMT is curative

ATG: Anti-thymocyte globulin

Higher response rates to horse ATG over rabbit ATG.

Scheinberg et al. NEJM 2011; 365: 430-8.

ATG: toxicities

1. During infusion: Fevers, shaking chills, rash/hives, low blood pressure, difficulty breathing

2. 2-3 weeks post-infusion: serum sickness. Fever, rash, pain in muscles/joints, abdomenalpain/diarrhea, neurological symptoms

3. Blood counts typically fall for the first few weeks (require intensive transfusion support)

4. Immunosuppression

8/29/2013

6

Cyclosporine (CsA): toxicities

-High blood pressure

-Kidney toxicity

-Low magnesium

-Increased body hair/facial hair

-Swollen gums

-Neurologic toxicities (eg: seizure)

-Immunosuppression

Major life-threatening complications of ATG/CsA

-Infection

Fungus

Bacteria

-Bleeding (eg: stroke)

Goal of ATG/CsA

• Blood counts often fail to return to normal

• Goals:

• transfusion-independence

• low risk of severe, life-threatening infections

• (Responses typically seen after ≈3-6 months after initiation of treatment. Some improvement may continue even 1 year post-therapy.)

Pt #: 119 146 51 42 77

*

Pediatric aplastic anemia: >70% response to ATG/CsA(Adults: 60-70% response rate)

Response a

t 6 m

onth

s (

%)

Yrs F/U: 3yr 5yr 10yr 10yr

Pediatric aplastic anemia: survival after ATG/CsA(Adults: 70-80%) Complications after ATG/CsA

• Failure to respond (refractory disease):

25-30%

• Relapse after initial response: 30%

• Clonal evolution (10-15% at 10 years)

– Prognosis varies with specific cytogenetic clones

8/29/2013

7

Maciejewski, J. P. et al. Blood 2002;99:3129-3135

Upfront treatment

Other immunosuppressive agents failed to improve response, relapse or clonal evolution:

MMF (Scheinberg et al. Br J Haematol. 2006: 133: 606-

611)

Sirolimus (Scheinberg et al. Haematologica. 2009; 94:

348-354)

Alemtuzumab (Scheinberg et al. Blood. 2012; 119: 345-354)

Small case reports/series suggest that tacrolimusmight be an alternative to CyA (Alsultan et al. Pediatr

Blood Cancer. 2009; 52: 626-630; Macartney et al, Pediatr Blood Cancer.

2009; 52:525-527)

G-CSF

No benefit for hematologic response or survival in randomized prospective trial

Association with clonal evolution in some retrospective studies

Consider in patients with active infection, persistent fever, or persistently low ANC

Cyclosporin taper

Gradual taper may minimize risk of relapse. Br J Haematol. 2008 Jan;140(2):197-205.

More rapid taper if serious side effects with CsA

Counts may continue to improve over long term

Yrs F/U: 3yr 5yr 10yr 10yr

Treatment of relapse

• Often responds to re-starting or

increasing dose of cyclosporin

• May require re-induction with ATG/CsA

or consideration of bone marrow

transplant

8/29/2013

8

Refractory AA

Persistence of severe AA 6 months following initiation of ATG/CsA

Consider unrelated donor bone marrow transplant

If no suitable donor, consider:

Second round of ATG/CyA (30-50% response)

Alemtuzumab (30-40% response) Scheinberg et al. Blood. 2012 119: 345-354

High dose cyclophosphamide (on study protocol)

Alemtuzumab (Campath)

-Antibody directed against CD52 which is found on the surface of lymphocytes

-Used in autoimmune diseases, lymphoid cancers, and transplants

-Prospective trial at NIH (Scheinberg et al., Blood 2012; 119: 345-354)

Hematologic response at 6 months:

Treatment-naïve: 16 patients

Non-responders to ATG/CsA: 27 patients

Relapse after ATG/CsA: 25 patients

Responses to Alemtuzumab

% r

espondin

g

Previously treated with ATG/CsA

Eltrombopag (Promacta)• Oral medication, stimulates the thrombopoietin

receptor (c-MPL) which is on the surface of megakaryocytes (which make platelets) and blood stem cells

• Olnes et al. NEJM 2012; 367: 11-19

• Treated 25 patients refractory to ATG/CsA for 12 weeks

• 11 (44%) had significant improvement in at least one blood cell type (many multilineage)

• 9 became independent of platelet transfusions

• 3 became independent of rbc transfusions

• 9 had improved neutrophil counts (median increase 1350)

High dose cyclophosphamide

-Comparable response rates compared to ATG/CsA

-?lower relapse rates and lower rates of clonal evolution?

-High rates of fungal infection

-Prolonged neutropenia and very delayed responses requiring intensive supportive care

-Currently recommended on investigational protocols

Supportive Care

8/29/2013

9

Supportive care: anemia

• Transfusion support (red cells)

– Indications: Symptomatic anemia (fatigue, exercise intolerance, rapid

heart rate and breathing, headache,

light-headedness, poor growth)

Supportive care: anemia

• Transfusion support (red cells)

– Risks:

-allosensitization: patient develops antibodies against the transfused red cells or platelets such that transfused cells are rapidly destroyed

-iron overload secondary to red cell transfusions

-initiation of subcutaneous desferalinfusions

-oral iron chelating medication (Exjade) is now available

-transfusion reaction

-infection

Clinical Complications of Iron Overload

• Liver disease with fibrosis and cirrhosis

• Cardiac failure, arrythmias

• Hypopituitarism:• central hypogonadism

• Growth hormone deficiency

• Central hypothyroidism

• Poor growth

• Diabetes mellitus

• Primary hypothyroidism

• Primary hypogonadism

• Hypoparathyroidism

Table 5: Iron Chelation Therapies

Route Toxicities Advantages Disadvantages Monitoring

Deferoxamine

(Desferal) SQ,IV

-skin irritation

-hearing impairment

-decreased vision

-skeletal abnormalities

-infection risk

(Yersinia)

-well defined

toxicity profile

-efficacy

-treatment of

cardiac iron overload

-inconvenience

-poor compliance

-infection and bleeding

risks with SQ infusions if

neutropenic or thrombocytopenic

-annual auditory and

visual testing

- liver iron annually

- cardiac iron and

cardiac function annually (after age 10)

Deferiprone

(L1) PO

-neutropenia

-arthritis

-hepatic fibrosis

-convenience (po)

-may enhance

cardiac iron

chelation

-possible lower efficacy

-toxicity profile

-not approved in US

-regular cbc with

differential

-ALT (monthly)

- liver iron annually

- cardiac iron and

cardiac function annually

(after age 10)

Deferasirox (ICL670,

Exjade)

PO

-GI

-rash

-renal

-transaminitis

-neutropenia

-convenience (po)

-low toxicity to

date

-relatively new

-limited longterm

experience

-creatinine (monthly)

-creatinine clearance

-ALT monthly

-liver iron annually

-cardiac iron and cardiac

function annually (after

age 10)

Iron Chelation Therapies

Supportive care: thrombocytopenia

• Transfusion support (platelets)

– Indications: Symptomatic (bleeding, increased bruising)

Prophylaxis: prior to surgical procedures

history of recurrent or serious bleeding

Key points:

For bleeding, evaluate other potential causes (eg: vitamin K deficiency, liver dysfunction)

Anti-fibrinolytic agents may be helpful (eg: Amicar)

Follow-up post-treatment

• Monitor blood counts

• Post-therapy bone marrow exam

• ?Regular bone marrow exams thereafter?

• Check marrow if blood counts

progressively fall without apparent cause