Thirty-six patients received allogeneic (34) or syngeneic (two) bone marrow transplants as treatment for severe aplastic anaemia or acute leukaemia. Nineteen of the allogeneic recipients received methotrexate (MTX) and 15 received cyclosporin A (CyA) as the predominant immunosuppressive agent to minimize graft-versus-host disease (GVHD) post transplant. In the first 100 d post transplant renal dysfunction was much less frequent in the MTX recipients than in the CyA recipients who exhibited three distinct syndromes of nephrotoxicity: most commonly. CyA recipients developed asymptomatic azotaemia, proteinuria, urinary casts, impaired urinary concentrating ability and hypertension. Secondly, two CyA recipients developed acute reversible renal failure precipitated by systemic bacterial infection which required dialysis and in which the kidney was the sole target organ; thirdly, two recipients of HLA-genotypically non-identical grafts developed a rapidly progressive fatal syndrome with multiple organ involvement including lung, brain and kidney which clinically and histologically resembled thrombotic thrombocytopenic purpura.
Ganciclovir was given prophylactically to 25 patients receiving allogeneic bone marrow transplants for haematological malignancy. Patients who were seropositive for cytomegalovirus (CMV) pre-transplant were given ganciclovir both pre- and post-transplant. Those who were CMV seronegative, but who received marrow from a CMV seropositive donor, received ganciclovir post-transplant. No nonhaemopoietic toxicity was observed. Toxicity was restricted to late reversible haematological toxicity in four of the 19 evaluable patients (one thrombocytopenia, one pancytopenia, two leucopenia). No CMV interstitial pneumonitis (IP) was observed, nor were any other clinically manifest CMV infections detected. Sixteen patients remain alive at greater than 84 to greater than 518 d post-transplant. In a retrospective comparison of 152 recipients of allogeneic transplants for haematological malignancy not given prophylactic ganciclovir, and in whom either the recipient or the donor or both were CMV seropositive, the incidence of all clinically manifest CMV infections was 23% (P = 0.02) and that of CMV IP 17% (P = 0.05). If only patients in the study group and the control group receiving the same cyclosporin/short methotrexate prophylactic immune suppressive regimen, the same prophylactic acyclovir regimen and the same CMV and leucocyte-filtered blood product transfusion strategy were considered, the incidence of all clinically manifest CMV infections in the control group was 24% (P = 0.01) and that of CMV IP 13% (P = 0.07). Ganciclovir appears to reduce the incidence of CMV infections in allogeneic marrow transplant recipients even in those given immune suppressive regimens associated with adequate control of acute graft-versus-host disease.
A prospective randomised trial was performed in patients given HLA-identical sibling bone marrow transplants for haematological malignancy comparing the combination of cyclosporin and methotrexate (CM) (n = 20) with the combination of cyclosporin, methotrexate and prednisolone (CMP) (n = 21) as prophylaxis for graft-versus-host disease (GVHD). There was no significant differences between the two arms for the incidence of acute GVHD grades I-IV, acute GVHD grades II-IV, chronic GVHD, interstitial pneumonitis, relapse, survival and disease-free survival. The actuarial incidence of acute GVHD grades II-IV in the CMP group was 10% and in the CM group 15% (ns). The incidence of leukaemic relapse in good risk patients was 42% in the CMP group and 40% in the CM group (ns), although the majority of these relapses were cytogenetic relapses only in patients with chronic myeloid leukaemia. The incidence of acute GVHD grades II-IV in both arms of the current trial was significantly lower than in our previous trial comparing cyclosporin and methotrexate as single agents. Leukaemic relapse is now the principal cause of treatment failure in this patient population. We conclude that prednisolone should not be included as part of the prophylactic GVHD regime and that further improvement in therapeutic outcome is dependent upon better control of the underlying malignancy.
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