Case 28 – summary

Case 28 explored the differential diagnoses to be considered when faced with  a patient with pancytopenia. We worked through a number of differentials during the case – see the previous update. However we concluded that our patient seemed to have primary or idiopathic aplastic anaemia.

The following is a note-like summary of some the most important aspects of managing a patient with Aplastic Anaemia.

Basics

• Trilineage cytopenia
• Usually elevated MCV at diagnosis
• ‘Empty’ trephine core
• Associated with various cytogenetic abnormalities: trisomy 6, trisomy 8, 13q-. Most of these have no impact on prognosis, although monosomy 7 does – these patients should be managed as an MDS and receive a BMT if fit, as there is a high transformation rate to AML.

Aetiology

• Mechanism: an immune attack on haemopoietic stem cells +/- the stromal environment.
• HLA-D2 is overrepresented in patients, suggests a role for antigen recognition.
• May have been preceded by seronegative hepatitis in 10% of cases.
• Can be caused by drugs and all suspect meds should be withheld; however long delays prior to rx should be avoided. Any drug in last 6 months could be implicated. Septrin, anti-convulsants, allopurinol, diclofenac, DMARDS all reported.
• Industrial chemicals etc can also cause MDS but are rarely identifiable by Hx and don’t change management.

Differential Diagnosis

• Hereditary bone marrow failure conditions – Fanconis Anaemia (test for chromosomal breakage in presence of mitomycin), Diamond Blackfan Anaemia, Dyskeratitis Congenita, Schwachmand Diamond Syndrome (metaphyseal shortening, exocrine pancreatic failure, short stature)
• Other differentials include:
  • Haemophagocytosis
  • Myelodysplasia (Hyoplastic variant)
  • PNH (overlap – see below)
  • TB/mycobacteria – haemophagocytosis, necrotic BM with granuloma
  • B12/folate deficiency
  • Hairy Cell Leukaemia.
  • Hypocellular ALL
  • SLE – AI pancytopenia with normal BM;

• Don’t miss Fanconi’s Anaemia: this is a DNA repair disorder and thus do not respond to IST (immunosuppressive therapy) , require v low dose conditioning for BMT, are at high risk of gynae and other malignancies lifelong, and need close monitoring for these. Although it is usually a childhood condition (elfin face, skeletal deformities) it can be diagnosed as late as the fourth decade.

• Telomeropathies, e.g Dyskeratitis Congenita, might be suggested by a FH of BMK/leukaemia, abnormal nails/skin/leukoplakia, pulmonary fibrosis, cirrhosis. Measurement of telomere length of lymphocytes using FISH
  • Distinguishes dyskeratosis congenita from AA
  • Abnormally short telomeres of lymphs = sensitive + specific for DC
• Screening for mutations in telomerase genes (DKC1, TERT, TERC)
  • DKC1, TERC, TINF2, NOP10, TERT mutations = Dyskeratosis Congenita
  • TERT / TERC mutations = Aplastic Anemia
• Hypocelluluar Myelodysplasia differentiated from AA by:
  • Presence of ALIPs (abnormal localization of immature precursors)
  • Islands of synchronous erythroid progenitors
  • Dysmegakaryopoiesis
  • Presence of abnormal karyotype

Classification

Severe AA:

• Peripheral Blood: 2 of 3
  • Granulocytes <0.5 x 10⁹/l
  • Platelets <20 x 10⁹/l
  • Reticulocytes <50 x 10⁹/l
• Marrow trephine: markedly hypocellular: <25% normal control

Very Severe AA as above but with – Neuts <0.2

Investigations

• Abdo exam/imaging – should NOT have hepatosplenomegaly
• Virology (hepatitis, CMV)
• PNH screen
• AI screen
• BM for A,T and cytogenetics (BM will show plasma cells etc; can see some haemophagocytosis)
• Mitomycin C breakage studies/telomere studies

Management

General:

• Transfusion – get extended phenotype or genotype first
• Plts only if bleeding (some authors suggest keeping plts >10)
• Prompt antibiotics for infection and prophylactic anti-fungals
• Tissue type sibs in younger patients.
• Iron chelation should be considered after 10-20 units of blood, esp if for BMT.

What doesn’t work:

• Epo, GCSF.
• Steroids – and these increase the risk of fungal infection.
• Watch&wait – spontaneous recovery is exceedingly rare.

Transplantation

• Historically – high rates of graft failure due to alloimmunisation from blood products and less effective conditioning regimes.
• Full intesnsity transplant (FIT) sibling donor – >80% cure.
• Great outcomes in kids, but poorer in adults and worse with age – correlates with increasing rates of GVHD.
  • GVHD has no clinical untility in AA, unlike in malignant diseases and should be avoided.
  • GVHD more likely if donor cells are PBSC rather than marrow.
  • MUD transplants are feasible in AA now – better typing, better supportive care – but little evidence to support its use c.f. sib allos. Both rejection and GVHD seem to be more common in MUD sources.
  • Need to match on high-res molecular level means donor pool is restricted.
  • Late relapse occurs – continue CyA for at least 9 months post transplant.

Immunosuppression

Response rate = 60-70% overall but relapse is common.

• ATG – Horse better than rabbit, though rabbit is more immunosuppressive.
• Other therapies, such as campath, are ineffective – degree of immunosuppression is not predictive of effect.
• Difficult medication to give – reactions: rigors, high fevers, hypotension, hypoxia; serum sickness, thrombocytopenia (keep plts >30), need for irradiated blood products, transaminitis.
  • Serum sickness: days 7-14 – joint pain, fever, rash
• Response may take up to 3 months (90%) but can occur up to 6 months after therapy. Counts may never normalise but improvement to transfusion and infection free state is only goal – don’t treat any further at this point.
• If no response after 6 months = refractory AA.
• In refractory disease rabbit ATG may be tried, or consideration of MUD transplant/ sib transplant in older patients.

Ciclosporin is commenced at the same time and maintained at target level of 200.Toxicities include hypertension, tremor, gingival hypertrophy, headache. Maintain for 1 year then start to taper.

Follow up

• Monitor counts, BM if they fall:
  • Look for clonal evolution – mono7 = MDS with poor prognosis – indication for BMT.
• 50% of patients responding to initial rx will relapse or evolve.
• Fertility not usually affected by BMT conditioning.
• In non-transplanted women – pregnancy will provoke a relapse in 1/3, but often improves again after delivery. May support with blood products and can use ciclosporin

Other options

• Androgens – useful in telomeropathies. E.g. oxymetholone
• Eltrombopag – in small cases series has lead to trilineage response – presumed to have a stem-cell-stimulating quality though not elucidated yet.

Thanks for joining the team for this case: see you again soon for another case from the fascinating world of haematology….