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Aplastic Anemia Current Thinking on the Disease, Diagnosis,

and Non-Transplant Treatment Options

Carlos M. de Castro, MD

Duke University Medical Center

Outline

• What is Aplastic Anemia? • What other diseases are similar? • How is it diagnosed? • Causes and associations • Classification of AA • Lab tests • Non-transplant treatment options

– Immunosuppressive therapy – Telomere diseases – Newer therapies

What is aplastic anemia?

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Aplastic anemia

• 1st described by Ehrlich in 1888

• Prognosis directly correlated with degree of cytopenias

• Prior to current therapies prognosis was poor

• Without transfusions, usual cause of death was heart failure, profuse hemorrhage, or overwhelming infection.

• With transfusion support, major cause of death was infection (bacterial or fungal)

Aplastic Anemia – Differential Diagnosis

• Aplastic anemia

• Hypocellular Myelodysplastic syndrome

• AA associated with PNH

• Inherited forms of bone marrow failure

Aplastic anemia Presentation

• Patients usually present with symptoms related to the low blood counts (cytopenias)

• Anemia causes fatigue, shortness of breath especially with exertion, palpitations and tachycardia.

• Thrombocytopenia leads to easy bruising, little red spots called petechiae, and bleeding.

• Low white blood cell counts may lead to recurrent infections.

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Inherited Bone Marrow Failure Syndromes

• “The inherited bone marrow failure syndromes are traditionally considered to be pediatric disorders, but in fact, many of the patients now are diagnosed as adults, and many diagnosed as children now live to reach adulthood…”

Blanche P Alter. “Diagnosis, Genetics, and Management of Inherited Bone Marrow

Failure Syndromes. ASH Education Book, 2007.

Known Inherited BMFs

• Fanconi anemia

• Dyskeratosis congenita

• Diamond-Blackfan anemia

• Schwachman- Diamond sydrome

• Severe congenital neutropenia

• Amegakaryocytic thrombocytopenia

• Thrombocytopenia- Absent Radii Syndrome (TAR)

Fanconi Anemia

• Autosomal recessive disorder associated with genomic instability.

• Characteristic birth defects include short stature, café au lait spots, hyper and hypo pigmentation, microcephaly, microphthalmia, and abnormal thumbs. 25% have no obvious physical deformity.

• Bone marrow failure, aplastic anemia, MDS, AML, as well as head & neck CA, and gyn CA may develop at an early age.

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Dyskeratosis congenita

• DKC or DC may present in adulthood and without any hematologic abnormality. Median age of presentation is 15 years.

• Diagnostic triad is lacey reticulated pigmentation, dysplastic nails, and oral leukoplakia.

• About 10% will develop CA, mostly solid tumors with median age around 28 years.

• Four genes – telomerase pathway.

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Aplastic anemia Causes and associations

• Drugs – Chloramphenicol – Gold salts – Anti-thyroid drugs – NSAID’s

• Chemicals – Benzene – Insecticides – Petrochemicals

• Viruses – Non-A, Non-B hepatitis – CMV – Parvovirus B19, EBV, Dengue, HIV ???

Aplastic Anemia - Pathophysiolgy

• Depletion of stem cells

• T-cell mediated immune assault

• Role of telomeres

Depletion of HSC

,Maciejewski JP et al. Blood 88: 1983, 1996.

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Aplastic Anemia - Pathophysiology

Aplastic anemia – Evidence of T-cell mediated attack

Aplastic anemia – Evidence of T-cell mediated attack

Risitano AM, et al. Lancet 364:355, 2004

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What is a telomere?

Telomerase complex

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• Acquired aplastic anemia (DKC)

• Liver cirrhosis

• Pulmonary fibrosis

Aplastic anemia – Diagnostic workup

• CBC with peripheral blood smear

• Bone marrow biopsy with cytogenetics (sometimes difficult)

• Rule out other causes (Fanconi’s)

• PNH screen

Classification of aplastic anemia

• Inherited vs acquired • Moderate aplastic anemia (MAA)

– Blood counts are low but not low enough to qualify as SAA

• Severe aplastic anemia (SAA) – Severe AA is defined by having 2 of 3 criteria:

• ANC <0.5/dl • plt < 20K/dl • Retic count < 1%

• Very severe aplastic anemia (VSAA) – ANC <0.2/dl

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Aplastic anemia Labs and tests to monitor

• CBC (Complete blood count) – WBC (White blood cell count) (normal 3.5-10) – Hemoglobin (normal 12-15) – Hematocrit (>38/40) – Platelet count (>150)

• Reticulocyte count (measures how many young RBC’s are being made)

• Differential – Neutrophil % or ANC

• When is a transfusion required?

Aplastic anemia A historical view of treatment

• Prior to the 70’s, severe aplastic anemia was almost universally fatal.

• Bone marrow transplantation was found to be curative.

• Immunosuppressive therapy (used to prevent GVHD from the transplant) led to hematologic improvement in some patients without the transplant.

• Led to a better understanding of the pathophysiology of the disease but also to further immunosuppressive therapies.

Aplastic anemia – Treatment options

• Horse antithymocyte globulin (ATG, ATGam) with Cyclosporin A + G-CSF

• Rabbit ATG

• Alemtuzumab (CAMPATH – 1H)

• Other immunosuppressive drugs?

• Androgens

• High dose cyclophosphamide

• Allogeneic bone marrow transplant

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Aplastic Anemia – Immunosuppression

Young NS et al. Blood 108: 2509, 2006

Predicting response to ATG

Scheinberg P et al. Br J Haematol 144:206, 2009.

Can we improve horse ATG + CyA?

Scheinberg P, Young NS. “How I Treat Acquired Aplastic Anemia” Blood 120:1185-1196, Aug 9, 2012

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ATG – Horse versus rabbit

ATG – Horse versus rabbit

Scheinberg P, Young NS. “How I Treat Acquired Aplastic Anemia” Blood 120:1185-1196, Aug 9, 2012

• 35 patients

• 58% response rate for SAA

• Adverse side effects including infections were minimal

Risitano AM, et al. British J Haematol 148:791-796, 2009

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Aplastic anemia – High dose cyclophosphamide

• 44 treatment naïve,

23 refractory

• OS at 20 years was 88%

• RR was 71%

Aplastic Anemia – Time Course

Young NS. Blood 108:2509, 2006

Aplastic Anemia – Time course

• Relapse – No consensus on how to define relapse – Decrease in blood counts to the point of becoming symptomatic

or needing transfusions – Up to 25%? – Treatment options include:

• Cyclosporine alone • ATG (horse or rabbit) • Alemtuzumab • Bone marrow transplant

• Clonal evolution to MDS/AML – Is the most concerning event as it portends a poor prognosis. – 10-15% of patients – Worsening blood counts, abnormal bone marrow, cytogenetics – Therapy includes MDS treatments, BMT

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Aplastic anemia – How to follow patients

Scheinberg P, Young NS. “How I Treat Acquired Aplastic Anemia” Blood 120:1185-1196, Aug 9, 2012

Scheinberg P et al. Br J Haematol 133:622, 2006

Aplastic Anemia – My approach

Initial Therapy:

Age < 20 – BMT if match available

Age 20-40 – Grey zone

Age > 40 – Immunosuppressive therapy

(Horse >Rabbit)

Telomere disease – Danazol?

Relapse > 12 months - retreat

Refractory or relapse < 12 months

Rabbit ATG

Alemtuzumab

High dose cyclophosphamide

BMT

Clinical trial?

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What does the future hold for Aplastic anemia?

• Can we manipulate the immune response better?

• Can we get stem cells to regenerate?

• Can we reduce the incidence of clonal evolution (MDS/AML)?

We have come a long way but still have a long way to go…

Aplastic anemia – which therapy is best?

Locasciulli A et al. Haematologica 92: 11, 2007