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]

Question 2 (10 marks)

Discuss the diagnosis and the management of the hepatic sinusoidal obstruction syndrome if it develops on day twelve. [8]

A full-mark answer reproduces the clinical and the laboratory criteria, the pathophysiology, the specific defibrotide therapy and the supportive care, and it acknowledges the severity and the mortality of the untreated disease. [8]

The clinical presentation and the diagnosis (3 marks). The sinusoidal obstruction syndrome, formerly the veno-occlusive disease, presents within the first twenty-one days of the conditioning with the weight gain from the fluid retention, the tender hepatomegaly, the rising bilirubin and the ascites. The pathophysiology is the injury to the hepatic sinusoidal endothelium by the conditioning, with the sloughing of the cells into the terminal hepatic venules and the obstruction that backs up the blood and starves the hepatocytes. The diagnosis is clinical, supported by the ultrasound with the doppler showing the reversal of the portal flow and the elevated hepatic pressures, with the transjugular liver biopsy and the pressure measurement in the selected case. The refined European Society for Blood and Marrow Transplantation criteria distinguish the classical and the late-onset forms and grade the severity. [8]

The defibrotide therapy (3 marks). Defibrotide is the only approved therapy for the severe sinusoidal obstruction syndrome, and it is started as soon as the diagnosis is suspected because the delay in the severe form is fatal. It is given at twenty-five milligrams per kilogram per day in four divided doses, as the intravenous infusion over two hours every six hours, for a minimum of twenty-one days and continued until the resolution plus a further seven days. Defibrotide protects the endothelium and restores the thrombolysis within the hepatic sinusoids without the systemic anticoagulation. The prophylaxis with the ursodeoxycholic acid, and the defibrotide for the high-risk child, is the contemporary standard for those with the identified risk factors. [10]

The supportive care and the severity (3 marks). The fluid restriction and the diuretics manage the ascites and the weight gain, the renal function is supported, and the child with the hepatorenal syndrome or the respiratory failure from the fluid overload is moved to the intensive care. The coagulopathy is corrected with the fresh frozen plasma and the vitamin K, and the thrombocytopenia is supported with the platelet transfusion. The severe form carries a mortality of over eighty percent when untreated, and the defibrotide cuts this sharply when started early, which is why the early recognition and the prompt therapy are the decisive interventions. [8]

Synthesis (1 mark). The fellow who can hold the clinical triad of the weight gain, the tender liver and the jaundice, who knows the defibrotide regimen, and who understands the severity of the untreated disease has the framework that carries the hepatic complication of the transplant. [10]