ISSN 1866-8836
Клеточная терапия и трансплантация

Pharmacokinetic comparison of cyclosporine A and tacrolimus for graft-versus-host disease prophylaxis

Moiseev Ivan S., Muslimov A. R., Pirogova Olga V., Darskaya Elena I., Slesarchuk Olga A., Bondarenko Sergej N., Afanasyev Boris V.

R. M. Gorbacheva Memorial Institute of Children Hematology and Transplantation, First State Medical University named I. P. Pavlov, Saint-Petersburg, Russia

Correspondence
Ivan S. Moiseev, PhD, Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, The First St.Petersburg State I. Pavlov Medical University, L. Tolstoy St 6-8, 197022, St. Petersburg, Russia
Phone: +7-812-233-29-25, E-mail: moisiv@mail.ru

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Cellular Therapy and Transplantation (CTT)
Volume 5, Number 1
Contents 

Summary

Introduction

There is a number of studies that compare cyclosporine A (CsA) and tacrolimus (Tac) for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (HSCT). Several large studies demonstrate superiority of Tac [1, 2]. Also a number of studies highlight pharmacokinetics (PK) significance for both CsA and Tac [3,4]. Nevertheless, a comparison of CsA and Tac along with PK analysis was not performed.

Patients and methods

Data from 93 patients (pts) with CsA and 209 pts with Tac GVHD prophylaxis was retrospectively analyzed. Detailed pts characteristics are presented in table 1. As the second component, a short-term course of methotrexate or MMF was used. Unrelated graft recipients also received horse ATG at the dose of 60 mg/kg. CsA and Tac concentrations were measured at least 2 times a week. Receiver operating curve (ROC) analysis was done to determine the most significant time frame of concentrations for GVHD development and cutoff values for CsA and Tac concentrations. Based on multivariate hazard ratio weights that included concentrations and number of time points with low concentrations, 3 groups of GVHD risk were distinguished and CsA and Tac pts were compared within these groups.

Results

In related HSCTs, here was no difference between CsA and Tac in the incidence of aGVHD grade II-IV (21% vs 22%, p=0,8) and grade III-IV (15% vs 14%, p=0,7), while in unrelated HSCT, GVHD grade II-IV incidence was comparable (49% vs 42%, p=0,2), and GVHD grade III-IV was lower with Tac (36% vs 23%, p=0,028). For CsA, the highest predictive value for aGVHD had median concentration within 30 days (AUC=0,62), and for Tac, a median within 21 days (AUC=0,62). The cutoff value for CsA was 163 ng/ml, and 9 ng/ml for Tac. For the same time frames, numbers of low concentrations of CsA (p=0,024) and Tac (p=0,021) were predictive for aGVHD. Based on these parameters, aGVHD II-IV rate was significantly different for CsA in the 3 model risk groups (27% vs 35% vs 60%, p=0,003) and Tac (23% vs 38% vs 48%, p=0,005). With intergroup comparison of unrelated grafts, there was no difference between CsA and Tac for aGVHD incidence in the low-risk (27% vs 23%, p=0,7) and intermediate-risk groups (35% vs 38%, p=0,8), whereas in the high-risk group, incidence of aGVHD II-IV (60% vs 48%, p=0,12) and aGVHD III-IV (45% vs 25%, p=0,041) was higher with CsA.

Conclusions

CsA and Tac have comparable efficacy as GVHD prophylaxis in related grafts. Superior efficacy of Tac in unrelated grafts is attributed to less severe impact of low drug concentrations on the incidence of aGVHD early post-transplant. Their efficacy is comparable if maintained within therapeutic limits >163 ng/ml for CsA and 9 ng/ml for Tac.

Parameter

CsA group, N=93

Tacro group, N=209

p-value

Male/Female

53/47%

49/51%

0,6

Age, median (range)

27 (18-60)

35 (18-67)

0,03

Donor

Related

Unrelated

Haploidentical

 

39%

59%

2%

 

32%

64%

4%

 

0,4

Graft source

Bone marrow

PBSC

 

37%

63%

 

35%

65%

 

0,9

HLA-mismatch

12%

8%

0,3

Diagnosis

AML

ALL

CML

MDS

other

 

46%

29%

16%

9%

0%

 

54%

33%

5%

5%

3%

 

0,06

Salvage, %

23%

23%

1,0

RIC/MAC

35%/65%

28%/72%

0,17

CD34+ x 106/kg

4,9±4,2

4,4±5,2

0,4

Table 1. Characteristics of groups.

References

  1. Nash RA, Antin JH, Karanes C et al. Blood. 2000; 96 (6): 2062-2068.
  2. Yanada M1, Emi N, Naoe T et al. Bone Marrow Trans- plant. 2004; 34 (4): 331-337.
  3. Mori T, Kato J, Shimizu T et al. Biol Blood Marrow Trans- plant. 2012; 18 (2): 229-234.
  4. Wilhelm AJ, de Graaf P, Veldkamp AI et al. Br J Clin Pharmacol. 2012; 73 (4): 553-563.

Keywords

Host-versus-gra disease, prophylaxis, cyclosporine a, tacrolimus, comparative efficiency


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