a plastic anemia

7/28/2019 A Plastic Anemia

1/23

Aplastic Anemia

Tissue Conference

1/19/00Brad Kahl, MD


2/23

Pancytopenia

Reduction of counts in all three cell lines

Differential Diagnosis

aplastic anemia

myelodysplasia

marrow replacement

leukemia, lymphoma, carcinoma, myelofibrosis

B12, folate

chemotherapy induced


3/23

Pancytopenia

Differential Diagnosis continued

splenomegaly (any cause)

PNH

SLE

Congenital

Fanconis, Schwamann-Diamond, Folate uptake def


4/23

Pancytopenia

Presentation varies with degree of cytopenia

anemia fatigue

thrombocytopenia bruising/bleeding

neutropenia infection

Approach

history

constitutional symptoms, pain, early satiety, etc...

diet, EtOH, exposures, occupation


5/23

Pancytopenia

Approach

PE

nodes, spleen, sensory, portal htn

Labs

B12, folate, LFTs, PNH, ANA

view smear (macrocytosis, megaloblastosis, teardrops, nuc RBCs, malignant cells)

abdominal imaging

bone marrow evaluation


6/23

Aplastic Anemia

Bone Marrow Failure

WHY??????????

Stem cell defect (seed)

Stromal cell defect (soil)

Growth Factor defect (fertilizer)

Evidence suggests that majority of cases ofidiopathic AA are due to immune suppression

of the hematopoietic stem cell


7/23

Aplastic Anemia Classification

Direct Toxicity

Iatrogenic (radiation, chemotherapy)

Benzene Drug metabolites

Immune Mediated

Drug metabolites

transfusion associated

hepatitis associated

idiopathic


8/23

Aplastic Anemia Pathophysiology

Evidence for an immunological basis arose

from observations after BMT

unexpected improvement of pancytopenia insome patients after allogeneic graft failure

successful BMT of identical twins generally

requires some sort of immunosuppressiveconditioning regimen


9/23


Evidence for stem cells (seed) as targets

in vitro colony forming assays are used to

define the stem cell compartment

two papers in 1996 showed profound deficits in

the stem cell population in patients with AA

at the time of clinical presentation the absolutenumber of stem cells is < 1% of normal


10/23


What about the stroma (soil) and growth factors

(fertilizer)?

successful BMT implies intact stroma since it is notreplaced in the transplant

laboratory studies have shown the stroma of AA

patients is able to support normal stem cell growth

stromal cells of AA patients tend to make increasedlevels of several growth factors (EPO, TPO, G-CSF)

clinical studies using factor replacement havent

worked


11/23


Laboratory Evidence for Immune

Destruction of Hematopoietic Stem Cells

mononuclear cells from blood and marrow ofAA patients suppress hematopoietic colony

formation by normal marrow stem cells

if selectively remove T cells from the sample,generally improve in vitro colony formation


12/23


What are the T cells doing?

Direct cellular cytotoxicity

blood and marrow of AA patients contain increasednumbers of activated cytotoxic lymphocytes

the number and activity of these cells decreases after

successful treatment with ATG


13/23


Cytokines

T cells of AA patients overproduce both IFN-gamma

and TNF-alphaboth of these cytokines inhibit colony formation in vitro

IFN-gamma induces nitric oxide synthase (NOS) and

production of nitric oxide (NO)

both induce expression of Fas receptor on CD34+ cells and

activation of this receptor by its ligand induces apoptosis

both appear to inhibit mitosis

IFN-gamma increases IFN regulatory factor 1 which inhibits

transcription of cellular genes and entry into the cell cycle


14/23



15/23


Inciting Events

much less clear, most cases--no clue

a few cases clearly associated with a non-A,non-B, non-C, non-G hepatitis

severe pancytopenia 1-2 months after an apparent

viral hepatitis

patients tend to have a marked activation of

cytotoxic lymphocytes and tend to respond

favorably to immunosuppressive therapy


16/23


Drugs

implicated in 15-25% cases (difficult to study)

no animal model

some cases may be a direct toxic effect

some cases appear immune mediated

in general patients have similar characteristicsas idiopathic AA and respond similarly to

immunosuppression


17/23

Aplastic Anemia Treatment

Options

BMT from donor vs. immunosuppression with

ATG, CSA, or ATG/CSA combinationsteroids, androgens generally ineffective

Trend towards separating severe AA and

non-severe AA in current clinical trials


18/23


Severe Aplastic Anemia Criteria

blood:

neutrophils < 500/mm

3

platelets < 20k

retics < 1% (corrected)

marrow

severe hypocellularity

moderate hypocellularity with hematopoietic cells representing

< 30% of residual cells

need 2/3 blood and one marrow criteria


19/23


Non-severe AA (Blood, April 99)

patients randomized to CSA vs. ATG/CSA

Overall Response Rate at 6 months

CSA 46% ATG/CSA 74% P=.02

Similar early toxicity/infections


20/23


Severe AA (Ann Int Med 1997)

Allo BMT vs. ImmunosuppressionORR 15 Yr OS

allogeneic BMT 89% 69%

Immunosuppression 44% 38%

40% BMT patients clinically extensive chronic GVHD

1/227 receiving immunosuppression got ATG/CSA

50/227 received ATG + mismatched bone marrow


21/23


Severe Aplastic Anemia

NEJM 1991 ORR

ATG/Pred 31%

ATG/Pred/CSA 65%

Blood 1992

ATG/LDM/oxymethalone 36%

ATG/HDM/oxymetholone 48% Blood 1995

ATG/CSA 78%


22/23


Future

High Dose Cyclophosphamide vs. ATG

Addition of MMF to ATG/CSA combinations

? allo BMT vs optimal immunosuppression?


23/23

Aplastic Anemia Summary

idiopathic AA appears to be an AI disorder

directed against hematopoietic stem cells

mediated by cytotoxic T cells and cytokines

allo BMT is the gold standard treatment

intensive immunosuppressive therapy has

improved the outlook for patients ineligible for

BMT due to age or lack of a suitable donor

expect further refinements in therapy as the

pathophysiology is further elucidated

a plastic anemia

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