Haematopoietic stem-cell transplantation: SAQ

This boy has a relapsed leukaemia that is the classic indication for the allogeneic transplant, and the task is to hold the donor selection, the conditioning, the prophylaxis and the early complications together, and to apply the specific management of the sinusoidal obstruction syndrome if it declares itself. The framework is the recognition that the allogeneic transplant confers the graft-versus-leukaemia effect at the cost of the graft-versus-host disease and the conditioning toxicity, and that the early complications are anticipated and monitored through the engraftment period. ^[1]

Question 1 (10 marks)

Outline the principles of the donor selection and the conditioning, the graft-versus-host prophylaxis, and the early complications you would anticipate and monitor for through the engraftment period. ^[4]

A full-mark answer covers the donor hierarchy and the HLA matching, the conditioning choice, the prophylaxis options, and the systematic monitoring for the acute graft-versus-host disease, the sinusoidal obstruction syndrome and the febrile neutropenia. ^[1]

Donor selection and the HLA matching (2 marks). The donor hierarchy moves from the matched sibling donor, the preferred source, through the matched unrelated donor, the haploidentical family donor and the cord blood unit. This boy has no matched sibling, so the matched unrelated donor is the appropriate next choice. The HLA matching examines the HLA-A, HLA-B, HLA-C and HLA-DRB1 at a minimum, so that an eight-out-of-eight match at these four loci is the standard for the unrelated donor, with the additional DQB1 and DPB1 refining the match. The permissive mismatches at the DPB1 are the contemporary refinement that the donor-selection algorithms apply. ^[1]

The conditioning (2 marks). The choice between the myeloablative and the reduced-intensity conditioning is driven by the disease, the comorbidity and the age. The myeloablative conditioning, with the total body irradiation or the high-dose busulfan, delivers the deepest graft-versus-leukaemia effect and is the standard for the aggressive relapsed leukaemia in this boy. The reduced-intensity conditioning, with the fludarabine and the lower-dose alkylator, relies more on the graft-versus-leukaemia effect and is reserved for the child with the comorbidity or the non-malignant disease. The conditioning empties the marrow and suppresses the recipient immunity so that the donor cells are accepted. ^[3]

The graft-versus-host prophylaxis (2 marks). The prophylaxis is the centrepiece of the post-transplant management. The traditional regimen is the calcineurin inhibitor, the cyclosporine or the tacrolimus, combined with the short-course methotrexate. The contemporary breakthrough is the post-transplantation cyclophosphamide at fifty milligrams per kilogram per day intravenously on days three and four, which selectively kills the rapidly proliferating alloreactive T-cells. The abatacept, added to the calcineurin inhibitor and the methotrexate, is approved for the prophylaxis in the unrelated donor transplant. ^[4]

The early complications and the monitoring (4 marks). The first two weeks bring the mucositis, the cytopenic sepsis and the febrile neutropenia, and the fever is treated with the antipseudomonal beta-lactam within one hour after the blood cultures. All the blood products are irradiated and leucodepleted throughout to prevent the transfusion-associated graft-versus-host disease. The engraftment period, from day ten to day twenty-eight, brings the rising counts and the lifting of the cytopenia, but it is also the window for the acute graft-versus-host disease and the sinusoidal obstruction syndrome. The neutrophil engraftment is monitored as the first of three consecutive days with an absolute neutrophil count of zero point five times ten to the nine per litre or above, and the donor chimerism is checked at the defined intervals to confirm the engraftment. The acute graft-versus-host presents with the rash on the palms and soles, the diarrhoea and the rising bilirubin, and the sinusoidal obstruction syndrome presents with the weight gain, the tender liver and the jaundice within the first twenty-one days. ^[12]