Optimal initial dose of oral cyclosporine in relation to its toxicities for graft-versus-host disease prophylaxis following reduced-intensity stem cell transplantation in Japanese patients

Abstract

Summary:Since the introduction of reduced-intensity stem-cell transplantation (RIST), allogeneic stem-cell transplantation has become available for elderly patients. While pharmacokinetics of cyclosporine might differ according to age or other factors, cyclosporine is uniformly started at an oral dose of 6 mg/kg/day. We retrospectively reviewed medical records of 35 patients aged between 32 and 65 (median 52) years who had undergone RIST. Doses of cyclosporine were adjusted to the target blood trough level of 150-250 ng/ml. Cyclosporine dosages were changed in 33 patients (94%). Dose reduction was required in 32 patients because of high blood levels (n ¼ 25), renal dysfunction (n ¼ 3), hepatic dysfunction (n ¼ 2), and hypertension (n ¼ 2). Cyclosporine doses were increased in one because of the suboptimal level. The median of the achieved stable doses was 3.1 mg/kg/day (range, 1.0-7.4). Five patients sustained Grade III toxicities according to NCI-CTC version 2.0: renal dysfunction (n ¼ 4), hyperbilirubinemia (n ¼ 2), and hypertension (n ¼ 2). No patients developed grade IV toxicity. There was no statistically significant difference in the frequency and severity of cyclosporine toxicities between patients aged 50 years and above and those below 50 years. The initial oral cyclosporine dose of 6 mg/kg/day was unnecessarily high irrespective of age. The possible overdose of cyclosporine might have aggravated regimen-related toxicities.

Influence of cyclosporine on the occurrence of nephrotoxicity after allogeneic hematopoietic stem cell transplantation: a systematic review

“…There was a predominance of cohort studies, 9,10,17,19,21–33 which were classified according to their scientific evidence as level 2B. In other words, they are trustworthy and good quality studies; thus, it is highly unlikely that new studies can show substantial changes regarding effects.…”

“…Almost all studies (89.5%) indicated an incidence of nephrotoxicity of more than 30%. 9,10,17–21,23–27,29–33 In other words, nearly one-third of patients undergoing HSCT and exposed to cyclosporine at doses from 5.0 to 12.5 mg/kg/day by oral administration developed some sort of kidney dysfunction. Cyclosporine was considered a risk factor for nephrotoxicity in 31.6% of the investigations.…”

Characterization of acute graft‐versus‐host disease following reduced‐intensity stem‐cell transplantation from an HLA‐identical related donor

“…Cyclosporine 3 mg/kg continuous infusion was initiated for GVHD prophylaxis from day 1, and this was switched to oral administration when patients tolerated oral intake. The doses were adjusted with its whole blood levels [31]. Nine patients received additional short-term methotrexate (10 mg/m 2 on day 1 and 7 mg/m 2 on days 3 and 6).…”

Cyclosporine use in Hematopoietic Stem Cell Transplantation: Pharmacokinetic Approach

“…CsA PKs barely studied in neonatal population. Along with introduction of reduced-intensity stem cell transplantation, more elderly patients have become candidates for allogeneic transplant [59] but data for elderly patients are limited as well. Some studies revealed that cyclosporine PKs is not different in elderlies compared with young adults but other observations including consequential toxicities have been controversial [59,93,[95][96][97] and accordingly some authors stated in favor of implementation of lower dosing and target levels in geriatrics [95].…”

“…The consistency with Neoral has provided the chance of starting immunomodulations with oral cyclosporine at early periods of transplantation process, reducing the need for initial iv. therapy [59][60][61][62][63][64][65]. Two other cyclosporine oral product brands, Cipol N ® and Equtrol ® demonstrated bioequivalency with Neoral [3, [66][67].…”