Aplastic anaemia and bone-marrow failure: SAQ

This boy has severe aplastic anaemia, meeting the Camitta criteria, and the question is how to grade it, how to exclude an inherited syndrome, and how to treat it. The marrow cellularity of 15 percent is under 25 percent, and he meets all three peripheral blood thresholds, so this is severe aplastic anaemia, and very severe by the neutrophil count of 0.3 times ten to the nine per litre. The normal karyotype and the absence of blasts make leukaemia and myelodysplasia unlikely, and the hypocellular marrow points to aplastic anaemia rather than marrow infiltration. [8]

Question 1 (10 marks)

Outline the diagnosis, the severity grading, and the investigations to exclude an inherited bone marrow failure syndrome. [8]

A full-mark answer addresses the Camitta criteria with the exact numbers, the severity grading, and the panel of tests that excludes the inherited syndromes before any transplant is planned. [8]

Diagnosis and severity (4 marks). The boy meets the Camitta criteria for severe aplastic anaemia, defined by a marrow cellularity under 25 percent with at least two of three peripheral blood thresholds. He meets all three: the neutrophils of 0.3 times ten to the nine per litre are under 0.5, the platelets of 12 times ten to the nine per litre are under 20, and the reticulocytes of 10 times ten to the nine per litre are under 60. The severity grade is very severe aplastic anaemia if the neutrophils fall under 0.2 times ten to the nine per litre, which this boy at 0.3 does not quite meet, though he is close and at high risk of sepsis. The normal karyotype and the absence of blasts exclude leukaemia and the hypocellular myelodysplastic syndrome, which are the chief differential diagnoses. [1][8]

Excluding the inherited syndromes (4 marks). Before any transplant is planned, the inherited bone marrow failure syndromes must be excluded, because the transplant conditioning regimen differs and the standard cyclophosphamide regimen is fatal in unrecognised Fanconi anaemia. The diepoxybutane chromosomal breakage test is the gateway test, performed on the peripheral blood lymphocytes, and it shows the increased chromosomal breaks and radial figures in Fanconi anaemia and is normal in the acquired disease. The telomere length assay by flow cytometry excludes the telomere biology disorders, and the next-generation sequencing panel for the inherited marrow failure genes confirms or excludes the rarer syndromes. The boy is examined for the radial ray anomalies, the café-au-lait spots, and the nail dystrophy that point to an inherited syndrome, and the family history of marrow failure, early greaying, or pulmonary fibrosis is taken. [9]

The HLA typing and the family screen (2 marks). The HLA typing of the boy and his siblings is done early, because a matched sibling donor makes the transplant the first line treatment, and the absence of one makes the immunosuppressive therapy the path. The family is counselled on the inheritance if an inherited syndrome is found, and the siblings are offered the testing. The full workup returns within a few weeks, and the treatment decision is made on the results. [8]

Question 2 (10 marks)

Explain the definitive treatment of severe aplastic anaemia, justifying each step with the relevant trial evidence. [3]

A full-mark answer reproduces the treatment fork, the immunosuppressive regimen with exact doses, and the appraisal of the key trials. [4]

The treatment fork (2 marks). The definitive treatment rests on a single decision made at diagnosis. The child with an HLA matched sibling donor is offered an allogeneic haematopoietic stem cell transplant as the first line treatment, because it is the only cure and gives the best survival, over 90 percent in children. The child without a matched sibling donor is offered immunosuppressive therapy, the combination that suppresses the immune attack and allows the marrow to recover. This boy, if he has no matched sibling donor, goes down the immunosuppressive path. [8]

The immunosuppressive regimen (4 marks). The regimen is horse antithymocyte globulin at 40 mg per kg per day for four days by intravenous infusion, with ciclosporin at 5 mg per kg per day adjusted to a trough of 200 to 400 nanograms per millilitre, and eltrombopag added from day 14 per the RACE trial. The German Aplastic Anemia Study Group trial of Frickhofen and colleagues in 1991 established the addition of ciclosporin to the antilymphocyte globulin, and the combination became the standard of care. The boy is premedicated with an antihistamine and a corticosteroid for the infusion reaction, and he is monitored for the serum sickness, the fever, the rash, and the arthralgia that appears in the second week. The response is assessed at three and six months, and the non-responder is offered the second line treatment. [3][8]

The choice of antithymocyte globulin (2 marks). The horse preparation is preferred over the rabbit, and the randomised trial of Scheinberg and colleagues in 2011 settled it. The trial showed a response rate of 68 percent at six months for the horse preparation against 37 percent for the rabbit, and the horse became the first line choice. The rabbit is reserved for the child who cannot tolerate the horse, never substituted on the grounds of tolerability alone. The fellow who remembers the 68 percent figure carries the key immunosuppressive fact. [4]

The eltrombopag and the RACE trial (2 marks). The eltrombopag is the modern addition, and the RACE trial of Peffault de Latour and colleagues in 2022 showed that adding it to the front line immunosuppression improved the complete response rate at three months. The eltrombopag is a thrombopoietin receptor agonist that stimulates the surviving stem cells to divide, and it carries a risk of clonal evolution, so the marrow cytogenetics are checked at the regular intervals. The fellow who holds the regimen, the horse over the rabbit choice, and the eltrombopag with its surveillance carries the evidence base of modern treatment. [7]