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Target blood concentrations of CYA and tacrolimus in randomized controlled trials for the prevention of acute GVHD after hematopoietic SCT

Bone Marrow Transplantation volume 45, pages 781–782 (2010)Cite this article

In a recent issue of Bone Marrow Transplant, Ram et al.1 reported a systematic review and meta-analysis of prophylaxis regimens for GVHD. They combined three randomized controlled trials that compared the combination of CYA and MTX (CYA–MTX) with the combination of tacrolimus and MTX (TAC–MTX), and concluded that although TAC–MTX was superior to CYA–MTX in terms of acute GVHD reduction, the incidence of all-cause mortality was similar.1, 2, 3, 4 A large retrospective study in Japan also revealed that the incidence of grades II–IV acute GVHD was significantly lower in patients who received TAC than in those who received CYA in matched unrelated donor transplantation, whereas no such difference was observed in matched sibling donor transplantation.5 Although it is difficult to directly compare the incidence of GVHD among these studies because of the difference in the study population, these findings suggest that although TAC is more effective than CYA for preventing acute GVHD, this benefit does not confer a survival benefit, probably because of increased toxicities.

However, before making such a conclusion, we have to consider whether CYA and TAC were administered at appropriate doses in these studies. Table 1 summarizes the design and results of the three randomized controlled trials. CYA was continuously infused with a target blood concentration between 150 and 450 ng/ml. This target concentration might have been too low, as the target concentration was equivalent to the target trough concentration that is widely accepted in European centers when CYA was administered twice daily.6 The target steady-state concentration in the continuous infusion of CYA should be higher than the trough concentration in twice-daily administration to provide an equal area under the concentration-time curve.7 In fact, in a retrospective study, the incidence of acute GVHD was significantly higher in patients who received a continuous infusion of CYA with a target concentration between 250 and 400 ng/ml than in those who received a twice-daily infusion of CYA with a target trough concentration between 150 and 300 ng/ml.8 In contrast, the target concentration of TAC was between 10 and 30 ng/ml in the two randomized trials in the United States and between 20 and 25 ng/ml in the Japanese trial. These target concentrations were apparently higher than that in current transplantation practice. Couriel et al.9 recommended a blood concentration of TAC between 8 and 12 ng per 100 ml based on their retrospective and prospective studies.

Table 1 Summary of the randomized controlled trials of CYA and tacrolimus (TAC)
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  1. Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan

    K Oshima, M Sato, K Terasako, S Kimura, S Okuda, S Kako & Y Kanda

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  1. K Oshima
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  2. M Sato
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Correspondence to Y Kanda.

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Oshima, K., Sato, M., Terasako, K. et al. Target blood concentrations of CYA and tacrolimus in randomized controlled trials for the prevention of acute GVHD after hematopoietic SCT. Bone Marrow Transplant 45, 781–782 (2010). https://doi.org/10.1038/bmt.2009.213

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