Transcript Aplastic Anemia

APLASTIC ANEMIA
Dr. Bhavesh S. Jarwani
APLASTIC ANAEMIA
Empty Marrow Syndrome
Is a disorder characterized by marked reduction or absence of
erythroid, granulocytic and megakaryocytic cells in the marrow
with resultant pancytopenia and reduced number of CD34+ and
colony forming cells.
Hematopoitic cell destruction by Immune
Mechanisms in Acquired Aplastic Anemia.
There is normal stromal cells but decreased number
of colony forming cells and stem cells as
it can be seen in Ps, radiographically, and also the
stem cells number
Immune Mechanics in Aplastic Anemia
• T cells:
mononuclear cells from the ps or marrow suppressed
the csf by the progenitor cells have elevated numbers
of the cytotoxic T Lymphocytes
• Cytokines:
peripheral blood from this patients had raised levels
of the soluble cytokines as y-INF and TNF and also
y-INF mRNA , evidence of the gene expression
• Incidence:
5-10 cases per million persons per year
• Age: Bimodal distribution
– young adults (15-30 years)
– elderly (above 60 years)
• Same incidence in Male and Female
• Geographic distribution
– more common in Asia than in North America and
Europe
Etiology
•
Acquired:
– Drugs: Antimetabolites, antimitotic agents, gold, chloramphenicol,
phenylbutazone and sulfonamides
– Radiation
– Chemicals: benzenes, Solvents, insecticides
– Viruses : Hepatitis A,B,C, E, G, and Parvo B19, CMV
– PNH
– Misc: pregnancy, connective tissue disorders, Graft-vs-Host disease
•
Hereditary:
– Fanconi’s Anemia
– Dyskeratosis congenita
– Shwachman Syndrome
•
Idiopathic:
– 50-65 % of cases
Etiology
• Drugs may be having direct dose dependent toxicity to the
marrow or having Idiosyncrasy to the drugs:
– Antineoplastic and antimetabolites are having direct dose
dependent toxicity
– Chloramphenicol having first immediate dose dependent toxicity
and long term Idiosyncrasy after one to two weeks later
• Radiation:
– Chronic exposure to low-dose and localized exposure leading to
development of aplastic anemia
• Benzene and insecticides:
– direct and also induction of the hapten leading to immune
mediated bone marrow suppression
• Virus:
– Hepatitis A,B,C,E and G. Parvovirus B19, CMV
• Pregnancy:
Etiology
• PNH:
– defect in PIG-A gene, so partial or complete inability to
construct Glycosylphosphatidylinositol(GPI) anchor for
the attachment of CD55, CD59
– diagnosis: Ham’s test, Flow cytometry using antibodies
against cell surface antigens CD55, CD59 which are
lacking in disease
• Congenital disorders:
– Fanconis Anemia
– Shwachaman syndrome
– Dyskeratosis congenita
Pathogenesis:
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Having stem cell defect: how?
Having immune mechanism in this disease progress
Evidence:
immunosupresion better results in BMT,
Better treatment with Antithymocyte globulin and
also immuno-suppression having comparable
results to BMT
• Activated T cells: overproduction of the cytokines
as interferon y and TNFb that in turn leading to
hematopoietic progenitors
How the destruction occurs:
• induction of the killing through programmed cell
death.
• Progenitor cells have Fas receptor , triggering
that though the cytokines induces the apoptosis.
• Also induces the production of the nitric oxide
by marrow cells that in turn leads to the cell
destruction
• transcription regulator is required, I.e. IRF,
interferon regulatory factor-1, and this is required
for the negative action of the INF-y.
ANTIGENS ENCITING APLASTIC ANEMIA:
• Either endogenous or exogenous:
– exogenous: hepatitis, drugs
– endogenous: somatic mutation in the HSC leading to autoimmunity
and at last the marrow failure immune response to peptides derived
from the aberrantly processed proteins like GPI
• Determinants of the autoimmunity:
– HLA class I and II are associated with many human autoimmune
diseases, HLA-DR2 is over expressed in American and Europe.
– specific class 2 haplotypes in Japanese that are respondent to the
CSA
• Drugs:
– genetically defined metabolic detoxification pathway in aplastic
anemia
Presentation of Anemia, Neutropenia and Thrombocytopenia
Hemorrhagic lesion of the gums in a patient with aplastic anemia caused by
infection with Capnocytophaga ochraceus; such lesions are easily confused with
those of herpes simplex.
26-year-old woman with acute aplastic anemia and 1 day of facial pain/swelling.
Mouth open involuntarily due to perioral edema. Needle aspirate of small
purplish area near right alar revealed P aeruginosa.
Diagnosis and differential Diagnosis
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Peripheral Smear
normocytic, and normochronic with low reticulocyte count index <2% .i.e.
hypoproliferative marrow
Bone Marrow
marrow spicules with empty fat cells and very few hematopoietic cells. Presence
of dysplasia suggest MDs, so as karyotype anomaly
suggest MDS.
Other tests:
LDH, haptoglobulin, hams test, flow cytometry to know about
PNH and also for fancony’s anemia
hairy cell Leukemia: cytochemical I.e. tartrate-resistent acid
phosphatase, and phenotypic, I.e. CD25+ monoclonal B cells
Classification:
Severe: when nautrophic <500, platelets <20,000/microL, and reticulocyte
<20,000/microL
Supersevere: when neutrophic count<200/microL
Characteristic
AA
HMDS
MDS
Abnormal
neutrophils
Abnormal mega.,
Increased blasts
Fibrosis
PNH
No
Yes
Yes
No
No
Absent
Yes
Sometimes
Occasional
Yes
Often
Occasional
15%
25%
4%
Progenitor cells
Very low
Low normal
Variable
Progress to Leu
Very low
25%
>25%
T cell activation
Yes
Yes
Yes
Increased TNF,
INKy
Yes
Yes
yes
• Course and prognosis of the disease:
– with transfusion support alone: 80 % of cases succumb to
death in 18 to 24 months, related to PMN count
– with MBT and Immunosuppresion: curative in 60 to 90 % of
cases, risk of CGVH threat
• Supportive care:
– transfusion of the blood products, CMV seronegative should
be given transfusion from the family members should be
avoided to prevent sensitization.
– pooled donor platelets but leads to sensitization
– in refractory cases need HLA matched transfusion
– packed cells filtrated to remove leukocyte and platelets
– iron overload : give chelating therapy deferoxamine
– CMV prophylaxis
– Staph. Aeureus * hospitalization * menses
• Treatment modalities:
– ATG: purified monomeric IgG from hyperimuune horse with human
thymocyte and thoracis duct lymphocytes
– 50 - 70 % good response
– 20-30 complete and durable recovery
– 70-80 have partial response
• Complication:
– MDS 30-6- %
– also secondary solid tumors
– response after 8 to 12 weeks
• Other drugs to suppress immunity:
– cyclosporine and cyclophosphamide and also high dose steroid
• Growth factors:
– Erythropoeitin, CG-CSF, GM-CSF, ILs 1,3, 6
• Response is slow
• Response is often incomplete
• Response may require successive course of
immunosuppression
• Relapse is common and require maintenance
therapy
• Evolution to clonal disease is common:
• Overall 15% of the cases develop clonal disease
like MDS or PNH
• Much higher after immunossuppression that BMT
Kinetics of the response to immunusuppressive treatment:
Relapse:
• Definition:
– Decrease in any of the peripheral cell counts to less than
50% of the median sustained counts during remission.
– Return of the counts to levels meeting the definition of
severe aplastic anemia.
– Or by resumed need of blood transfusion support.
• Risk: 35% at 11 years
– 45% at 5 years
– and reaches plateau at 64% between 7 to 10 years
Remission criteria:
Remission
Transfusions
Peripheral blood counts
Complete
No
All cell lines normal for age and
gender
Partial
No
Criteria for severe not met andOne
cell line improvement
Hb: +3 g/dL(is initial <6 gm/d
PMN +0.5*10^9/L(pre <0.5)
*2 (if pre >5*10^9)
Platelets+20*10^9/L(pre <20..
*2 ( if pre >20….)
No remission
Yes
Earlier criteria not met with
Relapse after initial treatment
Failure free survival in patients treated
with ALG and ALG+CsA
Drugs
Mechanism of action
Practice or in research
only
ATG
Depletion of T cells,
Tolerance, Induction??
In clinical practice
CSA
Block of cyclophilin A dependent In clinical practise
imuune activation, inhibition of
IL-2 and interferon –y
production
Cyclophosphamide
T cell depletion
Severe Aplastic Anaemia,
NIH
Anti-IL-2R
antibodies
Elimination of activated
lymphocyte
Moderate aplastic anemia,
pure red cell aplasia, and
NIH
Mycophenolic acid
Noncomeptitive reversible
inhibition of inosine
monophosphate dehydrogenase,
inhibition of T cell proliferation
With ATG and CSA in
children NIH, also for
relapse
Sirolimus
Inactivate of Protein kinase p70,
block in IL2 dependent
Only for solid organ
transplantation
Current and Future treatment strategies
• Evaluation of the best timing of immunosuppression
• Multidrug immunosuppression vs sequencial
immunosuppression
• Early retreatment with immunosuppression
• Improvement of current protocol
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dose of G-CSF
newer growth factors like stem cell factor
• New immunosuppresive protocol
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high dose cyclophosphamides
new immunosuppressive treatment