Aplastic anaemia and bone-marrow failure: Viva

This is a presentation of severe aplastic anaemia in a nine-year-old boy, meeting the Camitta criteria. The structured oral runs from the severity grading through the pathophysiology, the exclusion of the inherited syndromes, the treatment fork, and the trial evidence, and it ends with the long term counselling. [1]

Opening: grade the severity

Examiner. This boy has pancytopenia and a hypocellular marrow. How do you grade the severity, and what does the grade mean for the treatment? [1]

Candidate. The boy meets the Camitta criteria for severe aplastic anaemia, which is a marrow cellularity under 25 percent together with at least two of three peripheral blood thresholds. He has a cellularity of 15 percent, which meets the marrow criterion, and he meets all three blood thresholds: 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 grade is severe, and it is close to very severe, which is the neutrophils under 0.2 times ten to the nine per litre. The grade matters because the severe and the very severe disease are treated aggressively with the transplant or the immunosuppression, while the non-severe disease is often managed supportively. [1]

Branch 1: the pathophysiology

Examiner. Tell me why the marrow is empty. [4]

Candidate. The acquired aplastic anaemia is an immune disease in which a population of oligoclonal cytotoxic T cells expands and destroys the haematopoietic stem cell. The T cells release interferon-gamma and tumour necrosis factor-alpha, and these cytokines turn on the Fas death pathway on the stem cell, so the cell undergoes programmed death and the marrow is left fatty and empty. The immune mechanism is the reason the disease answers to the antithymocyte globulin, which depletes the T cells, and the ciclosporin, which blocks the T cell activation through the calcineurin pathway. [4]

Examiner (probe). And how do the inherited syndromes empty the marrow? [9]

Candidate. The inherited syndromes fail by a different mechanism. In Fanconi anaemia, the defective DNA cross-link repair means the stem cell accumulates chromosomal damage every time it divides, so it senesces and dies over the years of childhood. In the telomere biology disorders, the stem cell runs out of telomere because the telomerase is defective, so the cell stops dividing after too few divisions. Both end in the same hypocellular marrow, but the route is genetic rather than immune. [9]

Branch 2: excluding the inherited syndrome

Examiner. How do you exclude Fanconi anaemia in this boy, and why does it matter? [9]

Candidate. The diepoxybutane chromosomal breakage test is the gateway. It is done on a sample of the boy's peripheral blood lymphocytes, and it adds a cross-linking agent and counts the chromosomal breaks and the radial figures. The test is markedly increased in Fanconi anaemia and normal in the acquired disease. I also examine the boy for the radial ray anomalies, the café-au-lait spots, and the short stature of Fanconi anaemia, and I send the next-generation sequencing panel for the inherited marrow failure genes and the telomere length assay. It matters because the transplant conditioning differs: the standard cyclophosphamide regimen is fatal in unrecognised Fanconi anaemia, so the diepoxybutane test must be negative before any conditioning begins, and Fanconi anaemia uses a reduced intensity fludarabine based regimen. [9]

Branch 3: the treatment fork

Examiner. The boy has no matched sibling donor. What is his definitive treatment? [3]

Candidate. Without a matched sibling donor, the definitive treatment is immunosuppressive therapy, the combination of horse antithymocyte globulin at 40 mg per kg per day for four days, ciclosporin at 5 mg per kg per day, and eltrombopag added per the RACE trial. The German Aplastic Anemia Study Group trial of Frickhofen in 1991 established the addition of the ciclosporin to the antilymphocyte globulin, and the combination became the standard. If the boy had a matched sibling donor, the first line treatment would be the allogeneic haematopoietic stem cell transplant, which is the only cure and gives a survival over 90 percent in children. [3]

Examiner (probe). Horse or rabbit antithymocyte globulin, and why? [4]

Candidate. Horse, not rabbit. The randomised trial of Scheinberg in 2011 compared the two and showed a response rate of 68 percent at six months for the horse against 37 percent for the rabbit. The horse is the first line choice, and the rabbit is reserved for the child who cannot tolerate the horse, never the default. [4]

Branch 4: eltrombopag and surveillance

Examiner. Tell me about the eltrombopag and its risks. [7]

Candidate. Eltrombopag is a thrombopoietin receptor agonist added to the immunosuppression from day 14. The RACE trial of Peffault de Latour in 2022 showed that adding it improved the complete response rate at three months in the newly diagnosed disease. It stimulates the surviving stem cells to divide, which restores the trilineage haematopoiesis, but it carries a risk of clonal evolution, the emergence of a myelodysplastic clone. I monitor the boy with the marrow cytogenetics every three to six months, and the appearance of a clone such as a monosomy 7 redirects the treatment toward the transplant. [7]

Closing: the outlook

Examiner. Sum up the outlook for this boy. [7]

Candidate. With the modern immunosuppression of horse antithymocyte globulin, ciclosporin, and eltrombopag, the response rate is 60 to 80 percent at six months, and the responders recover a working marrow. The boy is monitored for the relapse, the clonal evolution, and the late myelodysplasia, and the non-responder or the relapser is offered the alternative donor transplant, which has improved with the fludarabine based conditioning. The inherited syndromes are excluded, the family is counselled, and the boy is followed into the adult service with the late risks in mind. [7]