Paeds · haematology-oncology-and-transfusion
Aplastic anaemia and bone-marrow failure
Also known as Aplastic anaemia · Severe aplastic anaemia · Bone marrow failure · Acquired aplastic anaemia · Inherited bone marrow failure syndrome · Hypocellular marrow
Fellowship guide to aplastic anaemia and inherited bone marrow failure in children. Covers the Camitta criteria for severe aplastic anaemia of marrow cellularity under 25 percent with two of three peripheral blood thresholds of neutrophils under 0.5 times ten to the nine per litre, platelets under 20 times ten to the nine per litre, and reticulocytes under 60 times ten to the nine per litre, the immune-mediated pathophysiology of cytotoxic T cell destruction of the haematopoietic stem cell, the inherited syndromes of Fanconi anaemia diagnosed by the diepoxybutane chromosomal breakage test, Diamond-Blackfan anaemia, dyskeratosis congenita, and Shwachman-Diamond syndrome, and the two definitive treatments of allogeneic haematopoietic stem cell transplant for the child with a matched sibling donor and immunosuppressive therapy of horse antithymocyte globulin at 40 mg per kg per day for four days with ciclosporin at 5 mg per kg per day and eltrombopag per the RACE trial for the child without one.
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- A pancytopenic child with a hypocellular marrow has severe aplastic anaemia until an inherited bone marrow failure syndrome is excluded by the diepoxybutane chromosomal breakage test
- A neutrophil count under 0.2 times ten to the nine per litre defines very severe aplastic anaemia and carries the highest risk of overwhelming sepsis
- Do not offer a sibling donor transplant in Fanconi anaemia until the sibling is confirmed negative by the chromosomal breakage test, because an undiagnosed carrier donor will engraft poorly
- A child on antithymocyte globulin who develops serum sickness with fever, rash, and arthralgia needs the infusion reviewed and the syndrome recognised, not mistaken for sepsis
- Eltrombopag in aplastic anaemia carries a risk of clonal evolution, so it is given with close blood count and marrow cytogenetic surveillance
- Rabbit antithymocyte globulin is inferior to horse antithymocyte globulin as first line therapy and must not be substituted on the grounds of tolerability alone
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- Recognises pancytopenia as the hallmark of marrow failure
- Applies the Camitta criteria for severe aplastic anaemia
- Initiates supportive care for the neutropenic febrile child
- Distinguishes acquired from inherited bone marrow failure syndromes
- Selects immunosuppressive therapy versus transplant by donor availability
- Monitors eltrombopag and ciclosporin for toxicity and clonal evolution
- Outlines the Camitta severity criteria with exact cell count thresholds
- States the horse antithymocyte globulin and ciclosporin regimen
- Explains why horse is preferred over rabbit antithymocyte globulin
- Elicates the stigmata of Fanconi anaemia and telomere biology disorders on examination
- Counsels the family on transplant versus immunosuppression
- Plans supportive care and infection prophylaxis during treatment
- Investigates pancytopenia with marrow biopsy and cytogenetics
- Recognises the inherited bone marrow failure syndromes
- Manages severe aplastic anaemia with contemporary immunosuppression
- Camitta criteria and severity grading
- Diepoxybutane chromosomal breakage test for Fanconi anaemia
- Mechanism of eltrombopag and its place in therapy
- Examination findings of inherited marrow failure syndromes
- Communication of the transplant decision
- Diagnoses severe aplastic anaemia by Camitta criteria
- Selects first line therapy by donor status
- Recognises Diamond-Blackfan and Fanconi anaemia
- Evaluates the pancytopenic child with a structured approach
- Applies the matched sibling donor transplant algorithm
- Monitors immunosuppressive therapy response and toxicity
- Applies Camitta criteria and severity grading
- Selects immunosuppression versus haematopoietic stem cell transplant
- Recognises inherited bone marrow failure syndromes
Overview & Definition
A marrow that falls silent, that empties itself of the cells it is meant to make, produces one of the most striking pictures in paediatric haematology. Aplastic anaemia is the syndrome in which the haematopoietic stem cell, the seed of every red cell, white cell, and platelet, is destroyed or fails to function, leaving a marrow that is fatty and empty and a blood count that is low in all three lineages at once. The child arrives pale, bruised, and bleeding, and the blood film shows pancytopenia, the simultaneous fall of the haemoglobin, the neutrophil count, and the platelet count. The bone marrow biopsy, the test that settles the direction, shows a hypocellular marrow with fat where blood-making tissue should be. [2]
The term bone marrow failure is the umbrella under which aplastic anaemia sits, and it carries the central distinction the fellow must hold. The failure is either acquired, in which a previously healthy marrow is injured, most often by an aberrant immune attack on the stem cell, or it is inherited, in which a genetic defect of the stem cell or its DNA repair sets the marrow up to fail over the years of childhood. Acquired aplastic anaemia is the more common, and it is largely an immune disease that answers to immunosuppression. The inherited syndromes, led by Fanconi anaemia, are rarer, they carry extra physical signs, and they change both the treatment and the counselling. [9]
Three ideas make this topic central to the fellowship exam. The first is the Camitta criteria, the numerical thresholds that define severe disease and that decide who is treated aggressively and who is watched. The second is the treatment fork, between the haematopoietic stem cell transplant offered to the child with a matched sibling donor and the immunosuppressive therapy offered to the child without one. The third is the inherited syndrome, especially Fanconi anaemia, whose diagnosis by the chromosomal breakage test and whose cancer risk shape the whole life of the family. The 2024 British Society for Haematology guideline of Kulasekararaj and colleagues is the current standard reference. [8]
References12ShowHide
- [1]Camitta BM, Thomas ED, Nathan DG, et al Severe aplastic anemia: a prospective study of the effect of early marrow transplantation on acute mortality. Blood, 1976.PMID 779871
- [2]Young NS, Kaufman DW The epidemiology of acquired aplastic anemia. Haematologica, 2008.PMID 18379007
- [3]Frickhofen N, Kaltwasser JP, Schrezenmeier H, et al Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. The German Aplastic Anemia Study Group. N Engl J Med, 1991.PMID 2017225
- [4]Scheinberg P, Nunez O, Weinstein B, et al Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med, 2011.PMID 21812672
- [5]Tisdale JF, Dunn DE, Geller N, et al High-dose cyclophosphamide in severe aplastic anaemia: a randomised trial. Lancet, 2000.PMID 11075769
- [6]Olnes MJ, Scheinberg P, Calvo KR, et al Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med, 2012.PMID 22762314
- [7]Peffault de Latour R, Kulasekararaj A, Iacobelli S, et al Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia. N Engl J Med, 2022.PMID 34986284
- [8]Kulasekararaj A, Cavenagh J, Dokal I, et al Guidelines for the diagnosis and management of adult aplastic anaemia: A British Society for Haematology Guideline. Br J Haematol, 2024.PMID 38247114
- [9]Auerbach AD Fanconi anemia and its diagnosis. Mutat Res, 2009.PMID 19622403
- [10]Alter BP, Greene MH, Velazquez I, et al Cancer in Fanconi anemia. Blood, 2003.PMID 12584146
- [11]Wlodarski MW, Vlachos A, Farrar JE, et al Diagnosis, treatment, and surveillance of Diamond-Blackfan anaemia syndrome: international consensus statement. Lancet Haematol, 2024.PMID 38697731
- [12]Bacigalupo A, Socie' G, Lanino E, et al. Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA Working Party. Haematologica, 2010.PMID 20494932