Transcript Aplastic Anemia

Aplastic Anemia
Tissue Conference
1/19/00
Brad Kahl, MD
Pancytopenia
• Reduction of counts in all three cell lines
• Differential Diagnosis
– aplastic anemia
– myelodysplasia
– marrow replacement
• leukemia, lymphoma, carcinoma, myelofibrosis
– B12, folate
– chemotherapy induced
Pancytopenia
• Differential Diagnosis continued
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splenomegaly (any cause)
PNH
SLE
Congenital
• Fanconi’s, Schwamann-Diamond, Folate uptake def
Pancytopenia
• Presentation varies with degree of cytopenia
– anemia
– thrombocytopenia
– neutropenia
fatigue
bruising/bleeding
infection
• Approach
– history
• constitutional symptoms, pain, early satiety, etc...
• diet, EtOH, exposures, occupation
Pancytopenia
• Approach
– PE
• nodes, spleen, sensory, portal htn
– Labs
• B12, folate, LFT’s, PNH, ANA
• view smear (macrocytosis, megaloblastosis, tear
drops, nuc RBC’s, malignant cells)
• abdominal imaging
• bone marrow evaluation
Aplastic Anemia
• Bone Marrow Failure
– WHY??????????
• Stem cell defect (seed)
• Stromal cell defect (soil)
• Growth Factor defect (fertilizer)
– Evidence suggests that majority of cases of
idiopathic AA are due to immune suppression
of the hematopoietic stem cell
Aplastic Anemia Classification
• Direct Toxicity
– Iatrogenic (radiation, chemotherapy)
– Benzene
– Drug metabolites
• Immune Mediated
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Drug metabolites
transfusion associated
hepatitis associated
idiopathic
Aplastic Anemia Pathophysiology
• Evidence for an immunological basis arose
from observations after BMT
– unexpected improvement of pancytopenia in
some patients after allogeneic graft failure
– successful BMT of identical twins generally
requires some sort of immunosuppressive
conditioning regimen
Aplastic Anemia Pathophysiology
• 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 absolute
number of stem cells is < 1% of normal
Aplastic Anemia Pathophysiology
• What about the stroma (soil) and growth factors
(fertilizer)?
– successful BMT implies intact stroma since it is not
replaced 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 increased
levels of several growth factors (EPO, TPO, G-CSF)
– clinical studies using factor replacement haven’t
worked
Aplastic Anemia Pathophysiology
• Laboratory Evidence for Immune
Destruction of Hematopoietic Stem Cells
– mononuclear cells from blood and marrow of
AA patients suppress hematopoietic colony
formation by normal marrow stem cells
– if selectively remove T cells from the sample,
generally improve in vitro colony formation
Aplastic Anemia Pathophysiology
• What are the T cells doing?
– Direct cellular cytotoxicity
• blood and marrow of AA patients contain increased
numbers of activated cytotoxic lymphocytes
• the number and activity of these cells decreases after
successful treatment with ATG
Aplastic Anemia Pathophysiology
• Cytokines
– T cells of AA patients overproduce both IFN-gamma
and TNF-alpha
– both 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
Aplastic Anemia Pathophysiology
Aplastic Anemia Pathophysiology
• 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
Aplastic Anemia Pathophysiology
• Drugs
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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 characteristics
as idiopathic AA and respond similarly to
immunosuppression
Aplastic Anemia Treatment
• Options
– BMT from donor vs. immunosuppression with
ATG, CSA, or ATG/CSA combination
– steroids, androgens generally ineffective
• Trend towards separating severe AA and
non-severe AA in current clinical trials
Aplastic Anemia Treatment
• Severe Aplastic Anemia Criteria
– blood:
• neutrophils < 500/mm3
• 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
Aplastic Anemia Treatment
• Non-severe AA (Blood, April 99)
– patients randomized to CSA vs. ATG/CSA
– Overall Response Rate at 6 months
• CSA 46%
ATG/CSA 74%
– Similar early toxicity/infections
P=.02
Aplastic Anemia Treatment
• Severe AA (Ann Int Med 1997)
• Allo BMT vs. Immunosuppression
ORR
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
Aplastic Anemia Treatment
• Severe Aplastic Anemia
– NEJM 1991
ATG/Pred
ATG/Pred/CSA
ORR
31%
65%
– Blood 1992
ATG/LDM/oxymethalone
ATG/HDM/oxymetholone
36%
48%
– Blood 1995
ATG/CSA
78%
Aplastic Anemia Treatment
• Future
– High Dose Cyclophosphamide vs. ATG
– Addition of MMF to ATG/CSA combinations
– ? allo BMT vs optimal immunosuppression?
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