Bone Marrow Transplantation (2014), 1–3 © 2014 Macmillan Publishers Limited All rights reserved 0268-3369/14 www.nature.com/bmt
LETTER TO THE EDITOR
Monitoring mycophenolate mofetil is necessary for the effective prophylaxis of acute GVHD after cord blood transplantation Bone Marrow Transplantation advance online publicatiion, 10 November 2014; doi:10.1038/bmt.2014.258
Use of mycophenolate mofetil (MMF), a novel immunosuppressant that inhibits T- and B-cell proliferation, together with a calcineurin inhibitor (CNI) has recently increased in cord blood transplantation (CBT) to reduce severe GVHD and pre-engraftment syndrome (PES).1,2 Wide interpatient variability has been reported in the plasma levels of mycophenolate (MPA), an active form of MMF, even after the same MMF exposure; however, few reports have performed therapeutic drug monitoring in CBT.3 Therefore, we performed a prospective cohort study to (1) determine the correlation between MPA concentration and incidence of severe PES or acute GVHD (aGVHD) after CBT and (2) compare the incidence of these complications with the historical cohort using CNI alone for GVHD prophylaxis after CBT. We continuously enrolled 24 adult patients who underwent single-unit CBT with GVHD prophylaxis using CNI and MMF at our department between September 2011 and December 2013. The protocols were approved by the Ethics Committee of Kyoto University. The historical cohort consisted of 38 patients who received single-unit CBT with GVHD prophylaxis using CNI alone between June 2003 and August 2011. Patient characteristics and CBT procedures are summarized in Table 1, and definition of transplantation risk and myeloablative conditioning regimens were in accordance with previous studies.4,5 MMF was orally administered at 10 mg/kg, three times a day (i.e. total dose=30 mg/kg/day) (with the exact intervals of 8 h), from Day 0 to Day 30. The MMF dosage was not modified during the clinical course after CBT. PES was defined as noninfectious fever with an unexplained skin rash before neutrophil engraftment.6 Severe PES was defined according to a previous report.2 Blood samples were collected immediately before and 1, 2 and 4 h after the morning administration of MMF on Day 7 (first week) and Day 21 (third week) after CBT. Total MPA levels in the plasma were measured using the enzyme multiplied immunoassay technique (EMIT)7 (C0, C1, C2 and C4, respectively), and C8 (which means the trough level of the next administration) was assumed to be equal to C0 values based on results of our preliminary analysis (n = 12 both at the first and third weeks) and other studies.3,8,9 Area under the curve (AUC)0–8 h was determined using the linear trapezoidal method, and the AUC0–24 h was calculated as 3 × AUC0–8 h. This method is one of the standards in the setting of MMF administration three times a day (every 8 h),3,8 because MPA concentrations reached to the peak within 2 h from administration, and decreased linearly after 4 h.9 Patients whose AUC0–24 h was below the lower quartile were categorized in ‘the lower concentration group’ at each time point (first and third week). We set our threshold at the lower quartile in order to find out the minimally required concentration of MPA AUC0–24 h to prevent PES and aGVHD effectively. Cumulative incidence of PES and aGVHD was calculated in each cohort using Gray’s method, and relapse or early death was considered a competing risk. Statistical analyses were performed
using R (The R Foundation for Statistical Computing, version 2.13.0). The alpha level of all the tests and the P-value were set at 0.05. MPA measurements revealed that C1 showed the highest values among the four points (mean ± s.d. in the first and third week; C0, 0.92 ± 0.87 and 0.92 ± 0.84 μg/mL; C1, 5.96 ± 3.88 and 5.47 ± 4.11 μg/mL; C2, 4.18 ± 1.87 and 3.63 ± 1.99 μg/mL; and C4, 1.56 ± 0.81 and 1.52 ± 0.97 μg/mL). The AUC0–24 h was 54.3 ± 21.9 μg h/mL (mean ± s.d.) in the first week and 50.0 ± 22.2 μg h/mL in the third week. The threshold of lower or higher MPA AUC0–24 h levels was set at 40 μg h/mL in both the first and third weeks, because the lower quartile values were 38.7 and 35.6 μg h/mL, respectively. As per results, severe PES was observed in two patients, whose AUC0–24 h in the first week was 23.0 μg h/mL (the lowest in the MMF cohort) and 84.0 μg h/mL (the third highest), indicating that severe PES may occur regardless of the MPA concentration. Actually, there was no statistical difference in the incidence of severe PES between the two groups in the first week (lower vs higher concentration groups; n = 7 vs n = 17; incidence 14.3% vs 5.9%, P = 0.53, respectively). The incidence of severe PES for the entire MMF group (8.3%) was significantly lower than that of the historical control cohort (CNI alone; 31.6%, P = 0.02) (Figure 1a). On the other hand, the incidence of aGVHD (grade 2–4) was significantly higher in the lower concentration group (n = 8) compared with the higher cohort in the third week (n = 16; 75.0% vs 31.2% on Day 100, P = 0.02; Figure 1b). This difference was still significant after adjusting for various confounding factors between the two groups (age, transplantation risk, conditioning regimens, donor-recipient sex and ABO mismatch and prior severe PES), and the relative risk was 8.05 (95% confidence interval 1.09– 59.7, P = 0.04). The incidence of aGVHD in the whole MMF group (45.8%) was similar to the historical cohort (39.5%, P = 0.72; Figure 1c). The relapse rate was unrelated to the MPA concentration (the higher AUC group, 22.8%; the lower group, 16.7% at 1 year; P = 0.76), and that rate was almost the same both in the entire MMF group and in the historical cohort (MMF group, 20.6%; historical cohort, 28.6% at 1 year, P = 0.54). As for infection, the incidence of severe bacterial infection (documented bacteremia up to Day 100) was 25.0% in the MMF group, similar to that in the historical cohort (31.6%, P = 0.62). The incidence of human herpes virus (HHV)-6 reactivation was higher in the MMF group (53.6% at Day 100) than in the historical cohort (34.2%, P = 0.15). There was no increase in the incidence of other viral or fungal infections. In the present prospective cohort study, we demonstrated that (1) a certain level of MPA is necessary to effectively prevent aGVHD after CBT and (2) severe PES can be reduced with the addition of MMF to CNI as GVHD prophylaxis. First, we observed that MPA levels and the AUC0–24 h widely fluctuated among patients and time points after CBT because the kinetics of MMF are drastically influenced by gastrointestinal damages caused by preparative regimens, loss of appetite and decreased oral intake or other drug interactions.10 However, appropriate concentrations are still not confirmed in patients who undergo CBT.1 We suggest
Letter to the Editor
2 Table 1.
Patient characteristics
Variables Sex Age (years) Disease Transplantation risk Donor-recipient sex mismatch Donor-recipient ABO mismatch NCC (×10E7 cells/kg) Conditioning TBI GVHD prophylaxis
CNI+MMF (n = 24)
Historical cohort (CNI alone, n = 38)
P-value
17/7 48.5 (19–65) 22/2 14/10 8/16 10/4/2/8 2.47 (1.90–3.76) 8/16 20/4 23/1
20/18 49 (18–65) 27/9 21/17 22/16 14/2/10/12 2.96 (1.51–5.40) 9/29 32/6 36/2
0.19 0.89 0.14 1.00 0.07 0.21 0.12 0.56 0.94 1.00
Male/female Median (range) Leukemia/lymphoma High/standard Y/N Major/minor/both/none Median (range) MAC/RIC Y/N FK506/CsA
Abbreviations: CNI = calcineurin inhibitor; MAC = myeloablative conditioning; MMF = mycophenolate mofetil; N = no; NCC = nuclear cell count; RIC = reducedintensity conditioning; Y = yes.
0.6 0.4 0.2 P = 0.02
0.0
10 20 Days after CBT
30
Number at risk
0.8 0.6 0.4 0.2 P = 0.02
0.0 0
20 40 60 80 Days after CBT
CNI alone group MMF + CNI group
1.0 Incidence of aGVHD
0.8
0
Lower group: 3wk AUC0-24hr ≤ 40 (μg hr/mL) Higher group: 3wk AUC0-24hr > 40 (μg hr/mL)
1.0 Incidence of aGVHD
Incidence of severe PES
CNI + MMF CNI alone group MMF + CNI group
1.0
0.8 0.6 0.4 0.2 P = 0.72
0.0 0
100
20
40
60
80
100
Days after CBT
Number at risk
Number at risk
CNI alone 38
27
26
25
Lower group 8
8
3
3
2
2
CNI alone 38
35
26
19
17
17
CNI + MMF 24
24
22
22
Higher group 16
16
14
12
11
10
CNI + MMF 24
24
17
15
13
12
Figure 1. Incidence of severe PES and aGVHD (grade 2–4) in each cohort. (a) Incidence of severe PES. The MMF group (including the lower and higher concentration groups) had a significantly lower incidence of severe PES compared with the historical cohort (CNI alone; P = 0.02). (b and c) Incidence of aGVHD (grade 2–4). (b) The lower concentration group had a significantly higher incidence of aGVHD than the higher group (P = 0.02). (c) The incidence was the same in the historical cohort (CNI alone) and the entire MMF group (P = 0.72).
that an AUC0–24 h of 40 μg h/mL in the third week should be the minimal requirement. In contrast, another group calculated AUC0–24 h just as the same strategy with ours, and reported that even AUC0–24 h o30 μg h/mL was sufficient to decrease the incidence of aGVHD in a small cohort study.3 Their patient characteristics, transplant procedures and strategies of MMF administration and AUC calculation were almost the same as those used for our patients. Therefore, these controversial data should be validated in large-scale prospective studies. Next, we demonstrated that even lower concentrations of MMF could reduce the incidence of severe PES compared with CNI alone. Severe PES may increase the risk of infection and organ dysfunction, leading to high rates of TRM.2 A previous study demonstrating that CBT after reduced-intensity conditioning regimens decreased the incidence of severe PES with GVHD prophylaxis using MMF plus CNI compared with CNI alone support our results.2 An increase in relapse was not shown in the MMF cohort, and the infection rate was almost the same except for HHV-6 reactivation. These data suggest that GVHD prophylaxis using MMF and CNI may be a more advantageous strategy compared with CNI alone. In summary, drug monitoring of MMF is necessary for the effective prophylaxis of aGVHD after CBT. This study has the limitation of a small patient number, so large-scale prospective studies are needed to substantiate our results and to determine the optimal GVHD prophylaxis regimen. Moreover, measuring the Bone Marrow Transplantation (2014), 1 – 3
levels of the unbound form of MPA11 or the activity of inosine monophosphate dehydrogenase isoenzymes12 may be necessary to analyze the direct effects of MMF on lymphocytes after CBT. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS This study was supported by research funding from the Ministry of Education, Science, Sports and Culture in Japan.
Y Arai1, T Kondo1, T Kitano1, M Hishizawa1, K Yamashita1, N Kadowaki1, T Yamamoto2, I Yano2, K Matsubara2 and A Takaori-Kondo1 1 Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan and 2 Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan E-mail: [email protected] REFERENCES 1 Minagawa K, Yamamori M, Katayama Y, Matsui T. Mycophenolate mofetil: fully utilizing its benefits for GvHD prophylaxis. Int J Hematol 2012; 96: 10–25.
© 2014 Macmillan Publishers Limited
Letter to the Editor
3 2 Uchida N, Wake A, Nakano N, Ishiwata K, Takagi S, Tsuji M et al. Mycophenolate and tacrolimus for graft-versus-host disease prophylaxis for elderly after cord blood transplantation: a matched pair comparison with tacrolimus alone. Transplantation 2011; 92: 366–371. 3 Wakahashi K, Yamamori M, Minagawa K, Ishii S, Nishikawa S, Shimoyama M et al. Pharmacokinetics-based optimal dose prediction of donor source-dependent response to mycophenolate mofetil in unrelated hematopoietic cell transplantation. Int J Hematol 2011; 94: 193–202. 4 Arai Y, Yamashita K, Mizugishi K, Watanabe T, Sakamoto S, Kitano T et al. Serum neutrophil extracellular trap levels predict thrombotic microangiopathy after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19: 1683–1689. 5 Arai Y, Yamashita K, Mizugishi K, Kondo T, Kitano T, Hishizawa M et al. Risk factors for hypogammaglobulinemia after allo-SCT. Bone Marrow Transplant 2014; 49: 859–861. 6 Patel KJ, Rice RD, Hawke R, Abboud M, Heller G, Scaradavou A et al. Pre-engraftment syndrome after double-unit cord blood transplantation: a distinct syndrome not associated with acute graft-versus-host disease. Biol Blood Marrow Transplant 2010; 16: 435–440. 7 Kodawara T, Yoshida Y, Sawada K, Masuda S, Yano I, Inui K-i. Evaluation of immunoassay (EMIT) for mycophenolic acid in comparison with high-
© 2014 Macmillan Publishers Limited
8
9
10
11
12
performance liquid chromatography. Jpn J Pharm Health Care Sci 2007; 33: 804–808. Jacobson P, El-Massah SF, Rogosheske J, Kerr A, Long-Boyle J, DeFor T et al. Comparison of two mycophenolate mofetil dosing regimens after hematopoietic cell transplantation. Bone Marrow Transplant 2009; 44: 113–120. van Hest RM, Doorduijn JK, de Winter BC, Cornelissen JJ, Vulto AG, Oellerich M et al. Pharmacokinetics of mycophenolate mofetil in hematopoietic stem cell transplant recipients. Ther Drug Monit 2007; 29: 353–360. Okamura A, Yamamori M, Shimoyama M, Kawano Y, Kawano H, Kawamori Y et al. Pharmacokinetics-based optimal dose-exploration of mycophenolate mofetil in allogeneic hematopoietic stem cell transplantation. Int J Hematol 2008; 88: 104–110. Frymoyer A, Verotta D, Jacobson P, Long-Boyle J. Population pharmacokinetics of unbound mycophenolic acid in adult allogeneic haematopoietic cell transplantation: effect of pharmacogenetic factors. Br J Clin Pharmacol 2013; 75: 463–475. Raggi MC, Siebert SB, Steimer W, Schuster T, Stangl MJ, Abendroth DK. Customized mycophenolate dosing based on measuring inosine-monophosphate dehydrogenase activity significantly improves patients' outcomes after renal transplantation. Transplantation 2010; 90: 1536–1541.
Bone Marrow Transplantation (2014), 1 – 3
LETTER TO THE EDITOR
Monitoring mycophenolate mofetil is necessary for the effective prophylaxis of acute GVHD after cord blood transplantation Bone Marrow Transplantation advance online publicatiion, 10 November 2014; doi:10.1038/bmt.2014.258
Use of mycophenolate mofetil (MMF), a novel immunosuppressant that inhibits T- and B-cell proliferation, together with a calcineurin inhibitor (CNI) has recently increased in cord blood transplantation (CBT) to reduce severe GVHD and pre-engraftment syndrome (PES).1,2 Wide interpatient variability has been reported in the plasma levels of mycophenolate (MPA), an active form of MMF, even after the same MMF exposure; however, few reports have performed therapeutic drug monitoring in CBT.3 Therefore, we performed a prospective cohort study to (1) determine the correlation between MPA concentration and incidence of severe PES or acute GVHD (aGVHD) after CBT and (2) compare the incidence of these complications with the historical cohort using CNI alone for GVHD prophylaxis after CBT. We continuously enrolled 24 adult patients who underwent single-unit CBT with GVHD prophylaxis using CNI and MMF at our department between September 2011 and December 2013. The protocols were approved by the Ethics Committee of Kyoto University. The historical cohort consisted of 38 patients who received single-unit CBT with GVHD prophylaxis using CNI alone between June 2003 and August 2011. Patient characteristics and CBT procedures are summarized in Table 1, and definition of transplantation risk and myeloablative conditioning regimens were in accordance with previous studies.4,5 MMF was orally administered at 10 mg/kg, three times a day (i.e. total dose=30 mg/kg/day) (with the exact intervals of 8 h), from Day 0 to Day 30. The MMF dosage was not modified during the clinical course after CBT. PES was defined as noninfectious fever with an unexplained skin rash before neutrophil engraftment.6 Severe PES was defined according to a previous report.2 Blood samples were collected immediately before and 1, 2 and 4 h after the morning administration of MMF on Day 7 (first week) and Day 21 (third week) after CBT. Total MPA levels in the plasma were measured using the enzyme multiplied immunoassay technique (EMIT)7 (C0, C1, C2 and C4, respectively), and C8 (which means the trough level of the next administration) was assumed to be equal to C0 values based on results of our preliminary analysis (n = 12 both at the first and third weeks) and other studies.3,8,9 Area under the curve (AUC)0–8 h was determined using the linear trapezoidal method, and the AUC0–24 h was calculated as 3 × AUC0–8 h. This method is one of the standards in the setting of MMF administration three times a day (every 8 h),3,8 because MPA concentrations reached to the peak within 2 h from administration, and decreased linearly after 4 h.9 Patients whose AUC0–24 h was below the lower quartile were categorized in ‘the lower concentration group’ at each time point (first and third week). We set our threshold at the lower quartile in order to find out the minimally required concentration of MPA AUC0–24 h to prevent PES and aGVHD effectively. Cumulative incidence of PES and aGVHD was calculated in each cohort using Gray’s method, and relapse or early death was considered a competing risk. Statistical analyses were performed
using R (The R Foundation for Statistical Computing, version 2.13.0). The alpha level of all the tests and the P-value were set at 0.05. MPA measurements revealed that C1 showed the highest values among the four points (mean ± s.d. in the first and third week; C0, 0.92 ± 0.87 and 0.92 ± 0.84 μg/mL; C1, 5.96 ± 3.88 and 5.47 ± 4.11 μg/mL; C2, 4.18 ± 1.87 and 3.63 ± 1.99 μg/mL; and C4, 1.56 ± 0.81 and 1.52 ± 0.97 μg/mL). The AUC0–24 h was 54.3 ± 21.9 μg h/mL (mean ± s.d.) in the first week and 50.0 ± 22.2 μg h/mL in the third week. The threshold of lower or higher MPA AUC0–24 h levels was set at 40 μg h/mL in both the first and third weeks, because the lower quartile values were 38.7 and 35.6 μg h/mL, respectively. As per results, severe PES was observed in two patients, whose AUC0–24 h in the first week was 23.0 μg h/mL (the lowest in the MMF cohort) and 84.0 μg h/mL (the third highest), indicating that severe PES may occur regardless of the MPA concentration. Actually, there was no statistical difference in the incidence of severe PES between the two groups in the first week (lower vs higher concentration groups; n = 7 vs n = 17; incidence 14.3% vs 5.9%, P = 0.53, respectively). The incidence of severe PES for the entire MMF group (8.3%) was significantly lower than that of the historical control cohort (CNI alone; 31.6%, P = 0.02) (Figure 1a). On the other hand, the incidence of aGVHD (grade 2–4) was significantly higher in the lower concentration group (n = 8) compared with the higher cohort in the third week (n = 16; 75.0% vs 31.2% on Day 100, P = 0.02; Figure 1b). This difference was still significant after adjusting for various confounding factors between the two groups (age, transplantation risk, conditioning regimens, donor-recipient sex and ABO mismatch and prior severe PES), and the relative risk was 8.05 (95% confidence interval 1.09– 59.7, P = 0.04). The incidence of aGVHD in the whole MMF group (45.8%) was similar to the historical cohort (39.5%, P = 0.72; Figure 1c). The relapse rate was unrelated to the MPA concentration (the higher AUC group, 22.8%; the lower group, 16.7% at 1 year; P = 0.76), and that rate was almost the same both in the entire MMF group and in the historical cohort (MMF group, 20.6%; historical cohort, 28.6% at 1 year, P = 0.54). As for infection, the incidence of severe bacterial infection (documented bacteremia up to Day 100) was 25.0% in the MMF group, similar to that in the historical cohort (31.6%, P = 0.62). The incidence of human herpes virus (HHV)-6 reactivation was higher in the MMF group (53.6% at Day 100) than in the historical cohort (34.2%, P = 0.15). There was no increase in the incidence of other viral or fungal infections. In the present prospective cohort study, we demonstrated that (1) a certain level of MPA is necessary to effectively prevent aGVHD after CBT and (2) severe PES can be reduced with the addition of MMF to CNI as GVHD prophylaxis. First, we observed that MPA levels and the AUC0–24 h widely fluctuated among patients and time points after CBT because the kinetics of MMF are drastically influenced by gastrointestinal damages caused by preparative regimens, loss of appetite and decreased oral intake or other drug interactions.10 However, appropriate concentrations are still not confirmed in patients who undergo CBT.1 We suggest
Letter to the Editor
2 Table 1.
Patient characteristics
Variables Sex Age (years) Disease Transplantation risk Donor-recipient sex mismatch Donor-recipient ABO mismatch NCC (×10E7 cells/kg) Conditioning TBI GVHD prophylaxis
CNI+MMF (n = 24)
Historical cohort (CNI alone, n = 38)
P-value
17/7 48.5 (19–65) 22/2 14/10 8/16 10/4/2/8 2.47 (1.90–3.76) 8/16 20/4 23/1
20/18 49 (18–65) 27/9 21/17 22/16 14/2/10/12 2.96 (1.51–5.40) 9/29 32/6 36/2
0.19 0.89 0.14 1.00 0.07 0.21 0.12 0.56 0.94 1.00
Male/female Median (range) Leukemia/lymphoma High/standard Y/N Major/minor/both/none Median (range) MAC/RIC Y/N FK506/CsA
Abbreviations: CNI = calcineurin inhibitor; MAC = myeloablative conditioning; MMF = mycophenolate mofetil; N = no; NCC = nuclear cell count; RIC = reducedintensity conditioning; Y = yes.
0.6 0.4 0.2 P = 0.02
0.0
10 20 Days after CBT
30
Number at risk
0.8 0.6 0.4 0.2 P = 0.02
0.0 0
20 40 60 80 Days after CBT
CNI alone group MMF + CNI group
1.0 Incidence of aGVHD
0.8
0
Lower group: 3wk AUC0-24hr ≤ 40 (μg hr/mL) Higher group: 3wk AUC0-24hr > 40 (μg hr/mL)
1.0 Incidence of aGVHD
Incidence of severe PES
CNI + MMF CNI alone group MMF + CNI group
1.0
0.8 0.6 0.4 0.2 P = 0.72
0.0 0
100
20
40
60
80
100
Days after CBT
Number at risk
Number at risk
CNI alone 38
27
26
25
Lower group 8
8
3
3
2
2
CNI alone 38
35
26
19
17
17
CNI + MMF 24
24
22
22
Higher group 16
16
14
12
11
10
CNI + MMF 24
24
17
15
13
12
Figure 1. Incidence of severe PES and aGVHD (grade 2–4) in each cohort. (a) Incidence of severe PES. The MMF group (including the lower and higher concentration groups) had a significantly lower incidence of severe PES compared with the historical cohort (CNI alone; P = 0.02). (b and c) Incidence of aGVHD (grade 2–4). (b) The lower concentration group had a significantly higher incidence of aGVHD than the higher group (P = 0.02). (c) The incidence was the same in the historical cohort (CNI alone) and the entire MMF group (P = 0.72).
that an AUC0–24 h of 40 μg h/mL in the third week should be the minimal requirement. In contrast, another group calculated AUC0–24 h just as the same strategy with ours, and reported that even AUC0–24 h o30 μg h/mL was sufficient to decrease the incidence of aGVHD in a small cohort study.3 Their patient characteristics, transplant procedures and strategies of MMF administration and AUC calculation were almost the same as those used for our patients. Therefore, these controversial data should be validated in large-scale prospective studies. Next, we demonstrated that even lower concentrations of MMF could reduce the incidence of severe PES compared with CNI alone. Severe PES may increase the risk of infection and organ dysfunction, leading to high rates of TRM.2 A previous study demonstrating that CBT after reduced-intensity conditioning regimens decreased the incidence of severe PES with GVHD prophylaxis using MMF plus CNI compared with CNI alone support our results.2 An increase in relapse was not shown in the MMF cohort, and the infection rate was almost the same except for HHV-6 reactivation. These data suggest that GVHD prophylaxis using MMF and CNI may be a more advantageous strategy compared with CNI alone. In summary, drug monitoring of MMF is necessary for the effective prophylaxis of aGVHD after CBT. This study has the limitation of a small patient number, so large-scale prospective studies are needed to substantiate our results and to determine the optimal GVHD prophylaxis regimen. Moreover, measuring the Bone Marrow Transplantation (2014), 1 – 3
levels of the unbound form of MPA11 or the activity of inosine monophosphate dehydrogenase isoenzymes12 may be necessary to analyze the direct effects of MMF on lymphocytes after CBT. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS This study was supported by research funding from the Ministry of Education, Science, Sports and Culture in Japan.
Y Arai1, T Kondo1, T Kitano1, M Hishizawa1, K Yamashita1, N Kadowaki1, T Yamamoto2, I Yano2, K Matsubara2 and A Takaori-Kondo1 1 Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan and 2 Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan E-mail: [email protected] REFERENCES 1 Minagawa K, Yamamori M, Katayama Y, Matsui T. Mycophenolate mofetil: fully utilizing its benefits for GvHD prophylaxis. Int J Hematol 2012; 96: 10–25.
© 2014 Macmillan Publishers Limited
Letter to the Editor
3 2 Uchida N, Wake A, Nakano N, Ishiwata K, Takagi S, Tsuji M et al. Mycophenolate and tacrolimus for graft-versus-host disease prophylaxis for elderly after cord blood transplantation: a matched pair comparison with tacrolimus alone. Transplantation 2011; 92: 366–371. 3 Wakahashi K, Yamamori M, Minagawa K, Ishii S, Nishikawa S, Shimoyama M et al. Pharmacokinetics-based optimal dose prediction of donor source-dependent response to mycophenolate mofetil in unrelated hematopoietic cell transplantation. Int J Hematol 2011; 94: 193–202. 4 Arai Y, Yamashita K, Mizugishi K, Watanabe T, Sakamoto S, Kitano T et al. Serum neutrophil extracellular trap levels predict thrombotic microangiopathy after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19: 1683–1689. 5 Arai Y, Yamashita K, Mizugishi K, Kondo T, Kitano T, Hishizawa M et al. Risk factors for hypogammaglobulinemia after allo-SCT. Bone Marrow Transplant 2014; 49: 859–861. 6 Patel KJ, Rice RD, Hawke R, Abboud M, Heller G, Scaradavou A et al. Pre-engraftment syndrome after double-unit cord blood transplantation: a distinct syndrome not associated with acute graft-versus-host disease. Biol Blood Marrow Transplant 2010; 16: 435–440. 7 Kodawara T, Yoshida Y, Sawada K, Masuda S, Yano I, Inui K-i. Evaluation of immunoassay (EMIT) for mycophenolic acid in comparison with high-
© 2014 Macmillan Publishers Limited
8
9
10
11
12
performance liquid chromatography. Jpn J Pharm Health Care Sci 2007; 33: 804–808. Jacobson P, El-Massah SF, Rogosheske J, Kerr A, Long-Boyle J, DeFor T et al. Comparison of two mycophenolate mofetil dosing regimens after hematopoietic cell transplantation. Bone Marrow Transplant 2009; 44: 113–120. van Hest RM, Doorduijn JK, de Winter BC, Cornelissen JJ, Vulto AG, Oellerich M et al. Pharmacokinetics of mycophenolate mofetil in hematopoietic stem cell transplant recipients. Ther Drug Monit 2007; 29: 353–360. Okamura A, Yamamori M, Shimoyama M, Kawano Y, Kawano H, Kawamori Y et al. Pharmacokinetics-based optimal dose-exploration of mycophenolate mofetil in allogeneic hematopoietic stem cell transplantation. Int J Hematol 2008; 88: 104–110. Frymoyer A, Verotta D, Jacobson P, Long-Boyle J. Population pharmacokinetics of unbound mycophenolic acid in adult allogeneic haematopoietic cell transplantation: effect of pharmacogenetic factors. Br J Clin Pharmacol 2013; 75: 463–475. Raggi MC, Siebert SB, Steimer W, Schuster T, Stangl MJ, Abendroth DK. Customized mycophenolate dosing based on measuring inosine-monophosphate dehydrogenase activity significantly improves patients' outcomes after renal transplantation. Transplantation 2010; 90: 1536–1541.
Bone Marrow Transplantation (2014), 1 – 3
