Acquired Aplastic Anaemia
Diagnosis § Peripheral blood cytopenia and reduced marrow cellularity (<30%), absence of infiltrate and no increased reticulin § At least 2 of: § Hb <10 § Plt <50 § Neu < 1.5
Exclusion of other causes of pancytopenia: § Congenital marrow failure, eg. Fanconi’s anaemia (AR) § FA cells show excessive chromosomal breakage when exposed to di-epoxybutane or mitomycin-C § Family history § Short stature, café au lait spots, skeletal abnormalities § Dyskeratosis congenita = leucoplakia, nail dystrophy, skin pigmentation § Hypoplastic MDS § Can be difficult to distinguish as the immune mechanisms involved in AA probably contribute to the cytopenia in MDS § Dyserythropoiesis and macrocytosis is common in AA, Pelger-Huet neutrophils more in keeping with MDS § ALIP § Cytogenetic abnormalities § PNH (flow cytometry +/- Ham) § Myelofibrosis § Hairy cell leukaemia § LGL leukaemia § Infections (TB, Histoplasmosis, HIV) § Liver disease (post hepatitic AA) § Haematinic deficiency § AI disease (SLE)
Incidence (4 per million) § Highest in E Asia x 4 § Biphasic § 10-25, >60yrs § M=F
Possible Causes § Majority idiopathic § Drugs § Chloramphenicol, sulphonamides, gold, penicillamine, diclofenac, carbimazole, dothiepin, chloroquine, clopidogrel § Occupation § Benzene, pesticides, cutting oils, ecstasy § Infection (EBV, CMV, Hepatitis (non A/B/C), HIV § Pregnancy § Thymoma / thymic carcinoma § GvHD § ALL § Particularly in children § Aplasia not distinguishable on haematological grounds from pure AA § Infections / splenomegaly / relative preservation of platelets may be clues § Aplasia lasts 3-6 weeks followed by a period of apparent recovery § ALL follows after 1-3 months § Treatment – early bone marrow transplant especially if a HLA identical sibling is available (can use transfusion to support whilst waiting for a donor) § Attempts to induce remission without transplant are often unsuccessful as the aplastic marrow often remains aplastic.
Severity § Non-severe = PMN >0.5 § Severe (<20% 1 year survival without treatment) § BM cellularity <25% or 2 out of 3 of: § PMN 0.2-0.5 § Plts <20 § Retics <20 § Very severe = PMN <0.2
Pathogenesis § 80% of idiopathic probably due to T cell mediated destruction of stem cells via IFN gamma and TNF § Microenvironment may also be a factor
§ Glycosyl-phosphatidyl-inositol (GPI) = anchors surfaces proteins to normal HSCs. § GPI-negative cells also exist as a result of somatic mutations in an X-linked gene, PIG-A. § CD52 is a GPI linked protein = alemtuzamab target § T-cell recovery after alemtuzumab is CD52-, ie. also GPI- = evidence that an antibody can select for GPI- cells. § In AA the emergence of a GPI- clone is predictive of response to IST. § GPI- cells could be spared from an auto-immune attack, suggesting that one of the putative antigens may be GPI linked. § Testing for GPI-linked antigens is now part of routine diagnostic and follow-up procedures. § Up to 25% may have a small PNH clone, but without evidence of haemolysis – significance of which is unclear
Treatment
1. Spontaneous recovery § Reasonable to wait up to 2 weeks if likely to be secondary to medication
2. Supportive care § Transfusion independent § Prophylactic antibiotics § Norethisterone § Dental hygiene / chlorhexidine mouthwash § Tranexamic acid
§ Transfusion dependent § CMV negative and leucodepleted products § (Irradiated products) § Consider apheresis / HLA matched plts (triggers <10 / 20 if septic) § Iron chelation
3. Immunosupressive therapy § Takes around 3 months to respond to treatment
ATG § Multiple antibodies CD3. CD5, CD11a, CD18, CD45, B2M – vary with preparation § Horse v. rabbit § Standard 1st line is horse ATG +CsA § 2nd line – horse again or rabbit, but if same prep used twice, higher rate of allergy and serum sickness Allergic reactions § Steroids/ antihistamines/ slow infusion (24hrs) § Usual course is 5 days § Cytopenia will be worse in the first few weeks Serum sickness § 75% develop 7-10 days following administration § Fever, arthralgia, rash, proteinuria but not renal failure § Prednisolone 1mg/kg should be started on d5 to help prevent this § Should be kept as inpatient for observation until risk of serum sickness over (14 days) § Anti-platelet effect § Platelets should be give before and after the infusion but not during it
§ ATG + androgens (eg. Oxymetholone) or CsA yield better response rates but not survival than ATG alone Response § Median time to response with ATG is 120days, therefore no second course before 4 months § 40-80% become transfusion independent § Delaying treatment >23 days increases risk of non-response. § ATG is not recommended in the presence of a significant PNH clone with evidence of haemolysis because of the risk of acute intravascular haemolysis during serum sickness § Second course can be given after 4-6 months if there is no response Relapse § Requiring transfusion after having been transfusion independant for at least 3 months § Risk of relapse is about 30% § Can be successfully rescued by an additional course of ATG § Vaccinations § May trigger relapse § Live polio vaccine to be avoided after ATG/ transplant
Cyclosporin § Can be used in combination with ATG – improves speed of recovery of counts and failure free survival but not overall survival § Can be used as a single agent when there are contraindications to ATG but significantly lower response rates § Recent data suggests starting to taper CsA at 12 rather than 6 months § Taper should be very slow (<10% dose/ month) § Taper for at least 1 year § Need to measure BP / renal function / levels
Prognostic factors after IST § Negative § Age >16yrs § < 20yrs 10yr survival = 73% § >40yrs 10yr survival = 47% § IST protocol other than ATG +CsA § Interval between diagnosis and treatment >23days § Neutrophil count had NO impact
Pregnancy after IST § Successful pregnancy is possible but associated with risk of relapse § Relapse more frequent in partial responders § Supportive care is the main stay of treatment with regular FBC § Experience from renal transplants suggest CsA may be safe
4. Growth Factors GCSF § Should not be used alone in early disease in the mistaken belief they may cure § Advantage = faster neutrophil recovery, and allows early identification of non-responders and therefore early referral for transplant § Disadvantage = expensive, no improved survival at 3 years § May be considered during severe systemic infections § High dose GSCF = no advantage § Epo – not recommended, most pts already have high epo levels, and concern re antibody formation and red cell aplasia Androgens § Used historically § Oxymthenalone shown in one trial to increase response rates to ATG § Virilising side effects / peliosis hepatis – therefore cyclosporin used more often
5. Bone marrow transplantation § Patients <20yrs with very severe AA are candidates for 1st line transplantation § Avoid transfusion pre transplant if possible as sensitisation to minor HLA antigens increases graft rejection rates § Good prognostic factors § Matched sibling donor § < 16yrs § Interval between diagnosis and transplant of <83days § No radiation § Survival in these groups = 91%
HLA-identical siblings § Conditioning with cyclophosphamide 200mg/kg and ATG § No infertility or secondary tumours § PB not recommended because of increased cGVHD § GVHD prophylaxis with CsA and MTX
§ EBMT is exploring low dose cyclophosphamide +low dose fludarabine + ATG in patients over 30yrs with encouraging results § Reduced TRM cf. with Cy alone Results § 70% 3 year survival § Retain fertility if cyclophosphamide conditioning used § 25% have chronic GVHD
Unrelated transplant donors § Candidates § Fully matched donor § <40yrs § Adults – failed at least 2 courses of ATG § Children – failed at least one § Severe AA § No evidence of active infection/ bleeding at time of transplant § Conditioning § Best results with lower dose radiation (2Gy) § EBMT currently testing FLU/CY/ATG and low dose radiation Results § Historically poor prognosis with only 30% disease free survival § More recent studies report improved prognosis probably due to better matching using high resolution HLA typing
Clonal evolution/ second malignancies § GPI- clone/ PNH § MDS § AML § Overall risk at 10yrs is 5-20% § Risk of MDS/ AML is significantly higher after IST cf. BMT, suggesting that MDS/ AML is assoc. with the IST as the conditioning for BMT is unlikely to eradicate a neoplastic clone § 2nd tumours more likely after radiation § Radiation currently not recommended for HLA-identical sibling transplants |
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