Review Tacrolimus: a New Agent for the Prevention of Graft-Versus-Host Disease in Hematopoietic Stem Cell Transplantation

Home , Tacrolimus

Bone Marrow Transplantation, (1998) 22, 217–225  1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt Review Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation

P Jacobson1, J Uberti2, W Davis1 and V Ratanatharathorn2

1College of Pharmacy, University of Michigan; and 2Blood and Marrow Stem Cell Transplantation Program, Division of Hematology/Oncology, Department of Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA

Summary: One of the challenges to reduce the morbidity and mortality after allogeneic bone marrow transplantation (BMT) is to Tacrolimus (FK506) is a macrolide lactone with potent improve the treatment and prevention of graft-versus-host immunosuppressive activity 100 times that of cyclosporine disease (GVHD).1 Currently, most regimens for GVHD by weight. The molecular mechanism of action is mediated prophylaxis are centered on cyclosporine as the main via an inhibition of the phosphorylase activity of calcineurin immunosuppressant given in conjunction with various by drug–immunophilin complex, resulting in the inhibition doses and schedules of methotrexate and/or methylpredni- of IL-2 gene expression. There are emerging studies now solone.2–5 Most clinical trials suggested the superiority of showing significant efficacy of tacrolimus in GVHD preven- a combination of cyclosporine and a short course of metho- tion in both related and unrelated donor transplantation. trexate over either agent alone. Yet, acute GVHD still Three multicenter randomized studies comparing tacrol- developed in 9–33% of patients who received a marrow imus to cyclosporine have been completed, one each in graft from an HLA-matched sibling donor.3,4,6–9 related and unrelated donor transplantation; the remaining Tacrolimus is a new immunosuppressive agent intro- study involved both related and unrelated donor transplan- duced into clinical trials for the prevention of acute GVHD. tation. All three studies showed a significantly lower inci- Emerging results of these trials suggest that tacrolimus has dence of grade II–IV acute GVHD in patients who received significant clinical efficacy, perhaps surpassing cyclospor- tacrolimus. One study in sibling donor transplantation ine for the prevention of acute GVHD. Nevertheless, tox- showed that patients with advanced disease who received icity associated with the use of tacrolimus can be substan- tacrolimus had a poorer survival than patients who tial. This paper will review the pharmacology of this agent, received cyclosporine, but the survival was similar in its toxicity and the clinical outcome of acute GVHD patients with non-advanced disease. The remaining two prophylaxis. studies, one in unrelated donors and the other combining both related and unrelated donors did not show any survival difference between the tacrolimus and cyclosporine Mechanism of action groups. In addition, this review also highlights some of the critical questions regarding the role of this agent in allo- Tacrolimus is a 23-membered macrolide lactone discovered geneic stem cell transplantation: (1) the contribution of in 1984 from the fermentation broth of a Japanese soil sam- methotrexate in combination with tacrolimus; (2) the start- ple that contained the fungus Streptomyces tsukuba- ing i.v. dose of tacrolimus; (3) the suggested whole blood ensis.10,11 Although tacrolimus has the molecular structure level of tacrolimus and its effect on nephrotoxicity; and (4) of a macrolide, it has limited antimicrobial activity. How- whether tacrolimus should be used in patients with ever, it has a potent inhibitory activity on T cell activation advanced malignancy. Future studies using tacrolimus in in both humans and mice.12–15 The in vitro activity of tacro- combination with other immunosuppressants, and its use limus was 100 times that of cyclosporine with the inhibitory in patients with advanced malignancy will be warranted. concentrations (IC50) of 0.1 nmol/l and 10 nmol/l, respect- Keywords: allogeneic bone marrow transplantation; tacrol- ively.16 Clinically, tacrolimus has not only shown substan- imus; graft-versus-host disease; FK506; peripheral blood stem tial efficacy in the rescue of liver graft rejection,17 but also cell transplantation in the prevention of liver18, kidney19–21 and cardiac graft rejection.22,23 Despite the structural differences between tacrolimus and cyclosporine, they share similar mechanisms of action at the molecular level. Both drugs mediate their activity through binding to an immunophilin.24,25 Tacrolimus binds Correspondence: Dr V Ratanatharathorn, Associate Professor of Internal Medicine, B1–207 Cancer Center, University of Michigan Medical Center, to an immunophilin–FK binding protein-12 (FKBP12) to 1500 E Medical Center Drive, Ann Arbor, MI 48109–0914, USA form an active tacrolimus–FKBP12 complex. This complex Received 30 January 1998; accepted 30 March 1998 inhibits the phosphorylase activity of calcineurin, thus pre- Tacrolimus for the prevention of GVHD P Jacobson et al 218 Ϯ venting the translocation of NFAT (nuclear factor of acti- whole blood Vd was 1.67 1.02 l/kg after a single intra- vated T cells) into the nucleus and resulting in an inhibition venous dose of 0.02 mg/kg administered over 4 h.32 of IL-2 gene expression. Moreover, tacrolimus is capable of abrogating the conversion of precursor helper T lympho- Metabolism and elimination cytes to antigen-conditioned helper T lymphocytes in an in vivo model, whereas cyclosporine at 20-fold higher concen- Tacrolimus is extensively metabolized by the mixed func- trations failed to exert this effect.26 This differential effect tion oxidase system, primarily the cytochrome P450IIIa4 may have important biologic consequences by abrogating system in the liver, and possibly the small intestine.27,38–41 the critical step of the immunologic cascade leading to Less than 1% of an intravenous or oral dose is found in organ rejection or graft-versus-host disease. the urine.27,42 The drug undergoes demethylation, hydroxyl- ation and conjugation in the liver with most of the metabolites, and possibly conjugates, of tacrolimus eliminated in Pharmacokinetics the bile.27,40,43 Although many metabolites exist, their immunosuppressive activity is not well characterized.27,40,44 Absorption Tacrolimus clearance determined by whole blood ELISA analysis was studied in 17 BMT patients on day 11 post- The bioavailability of tacrolimus after oral administration transplant.33 These patients received either tacrolimus 0.03 in healthy volunteers varies from 14 to 17%. However, it mg/kg by continuous intravenous infusion alone or in com- is highly variable in solid organ transplant recipients, rang- bination with methylprednisolone or methotrexate. The ing from 4 to 89% with a mean of 25%.27–30 This variability clearances were 0.075 Ϯ 0.048, 0.055 Ϯ 0.023 and in absorption is not well understood, but may be due to 0.063 Ϯ 0.032 l/h/kg, respectively, and these were not sig- incomplete absorption resulting from poor solubility in gas- nificantly different. Pharmacokinetics were also described tric fluids, admixture with food, or changes in gut motility in another 12 BMT patients who received intravenous bolus and metabolism.30,31 In liver transplant patients, food of 0.02 mg/kg over 4 h.32 The half-life and clearance were reduces the bioavailability of tacrolimus by 27 Ϯ 18.2% 18.2 Ϯ 12.1 h and 0.071 Ϯ 0.034 l/h/kg, respectively. when compared to the fasting state.30 Unlike cyclosporine, tacrolimus is not dependent on bile for absorption. The absorption of tacrolimus in orthotopic liver transplant Efficacy in bone marrow transplantation recipients is similar regardless of the clamping of the T- tube. Therefore, dosage adjustments are unnecessary in The efficacy of prophylactic tacrolimus for GVHD in bone patients with biliary obstructions.28 marrow transplantation was documented in two animal A pharmacokinetic study was conducted between days model systems. In the murine model, Blazar et al45 demon- 23 and 43 in 11 BMT recipients who received tacrolimus strated the reduction of mature T cell expansion in response as a single agent for GVHD prophylaxis.32 The whole blood to host alloantigens, resulting in a lower incidence of lethal concentration of tacrolimus peaked at 2.0 Ϯ 1.6 h with a GVHD. Tacrolimus also prevented the rejection of T cell- bioavailability of 32 Ϯ 24%. The bioavailability of tacrol- depleted marrow allografts via a similar cellular mech- imus was modified by the concomitant administration of anism. Using the canine model, long-term survival was methotrexate and methylprednisolone.33 The mean bioavail- found in five of 10 recipients of DLA-mismatched marrow ability of tacrolimus was significantly lower in the patients and buffy coat when tacrolimus was given in conjunction who received methotrexate (16 Ϯ 8%) when compared to with a short-course of methotrexate.46 patients who received either tacrolimus alone (49 Ϯ 10%) or tacrolimus in conjunction with methylprednisolone (27 Ϯ 12%). The decreased bioavailability in patients who Treatment of GVHD received methotrexate was attributed to heightened radi- Earlier reports on the use of tacrolimus in clinical bone ation-induced gastroenteritis. marrow transplantation centered on the treatment of resistant acute and chronic GVHD, especially in patients who Distribution were resistant to steroids. In six children with steroid-resistant grade III–IV acute GVHD treated with tacrolimus, Tacrolimus is highly bound to plasma proteins (75 to 99%) improvement was seen in the skin (6/6), gut (6/6) and liver including alpha-1 acid glycoprotein, albumin, lipoproteins (3/4).47 In a Japanese study,48 tacrolimus was given to 18 and globulins.30,34,35 The drug rapidly distributes from patients with acute GVHD unresponsive to cyclosporine or plasma into the red blood cells. The high affinity of tacrol- other immunosuppressants. Out of 13 evaluable patients imus for red blood cells may be due to the high intracellular with acute GVHD, seven responded. In the same report, 12 content of FKBP.35,36 Measurable concentrations of tacrol- of 26 (46%) additional patients with chronic GVHD (seven imus are present in the lungs, spleen, heart, kidney, pan- with localized disease and 19 with extensive disease) creas, brain and liver.27 Therefore, the volume of distri- responded to tacrolimus. The investigators at the University bution (Vd) of tacrolimus in plasma and blood is large and of Pittsburgh treated adult patients who had steroid- or variable, ranging from 0.85 to 65 l/kg.29–31,37 Because this cyclosporine-resistant GVHD (six acute and 24 chronic) variation is partly due to binding of tacrolimus to RBC, and three patients who were intolerant to cyclosporine.49 the Vd determined by whole blood assay is lower than that Twelve patients (36%) responded and survived with determined by plasma concentrations. In BMT patients, the reduced steroid requirements. None of these studies were Tacrolimus for the prevention of GVHD P Jacobson et al 219 well controlled in terms of patient selection and response conducted by the Japanese FK506 BMT Study Group evaluation. Therefore it is difficult to define the role and which included both advanced and non-advanced did not efficacy of tacrolimus in the treatment of GVHD. show a difference in survival.50 In unrelated donor transplantation, there are three single institution studies55–57 and two multicenter studies.50,58 The Prevention of GVHD three single institution studies reported grade II–IV acute At present, there are 11 published studies evaluating the GVHD rates ranging from 34–50%. Two multicenter stud- role of tacrolimus in the prophylaxis of acute GVHD in ies randomized patients to receive either tacrolimus or allogeneic transplantation. We have summarized the results cyclosporine; one was conducted in North America and the of seven studies in related donor transplantation in Table 1, other was conducted by the Japanese FK506 BMT Study and five studies in unrelated donor transplantation in Group.50,58 The North American study limited patient eligi- Table 2 (one report included both related and unrelated bility to those with non-advanced disease. The Japanese donor transplantation50). study included some patients with advanced disease. Both In the related donor transplant studies, five were single- studies reported a lower rate of grade II–IV acute GVHD center or limited institutional studies in patients with hema- in patients randomized to the tacrolimus arm with no differ- tologic malignancies.32,33,51–53 Collectively, there were 153 ence in survival. patients treated with tacrolimus and the incidence of grade Thus far, clinical trials have demonstrated substantial II–IV acute GVHD was 15–44%. The other two studies efficacy of tacrolimus for the prevention of acute GVHD, were multicenter randomized trials comparing tacrolimus and also suggest the superiority of this agent over cyclospo- with cyclosporine. Both of these studies showed a signifi- rine. These studies also raised several important practical cantly lower incidence of grade II–IV acute GVHD in questions. First, what was the contribution of methotrexate patients randomized to the tacrolimus arm. In the North to the overall immunosuppressive activity of tacrolimus/ American trial,54 the overall survival was worse in the tac- methotrexate? Most investigators favor the combination of rolimus arm. The poor survival in the tacrolimus arm was tacrolimus and methotrexate, perhaps because of experi- confined to patients with advanced disease (patients whose ence with cyclosporine/methotrexate which has proven to malignancies were not in remission or who had CML not be superior to cyclosporine alone. Although two studies in first chronic phase), whereas there was no survival differ- reported tacrolimus monotherapy to be effective in GVHD ence between the two arms consisting of patients with non- prophylaxis, there is no randomized study comparing advanced disease (patients with CML in first chronic phase tacrolimus/methotrexate to tacrolimus monotherapy.32,52 In or whose malignancies were in remission). The other study contrast to cyclosporine,2 the cumulative dose of metho-

Table 1 Transplants using related donor and tacrolimus for acute GVHD prophylaxis

Ref. Median age in years GVHD prophylaxis n Source of stem cells % Acute GVHD TBI/Non-TBI (range) grade II–IV preparative regimen (% TBI)

Fay32 40 Tacro 27 Marrow 41 19/8 (63) (18–53) 27 matched Nash33 Ͻ35 n = 9 Tacro 6 Marrow 44 17/1 (94) Ͼ35 n = 9 Tacro/MTX 5 18 matched Tacro/steroid 7 Uberti51 41 Tacro/MTX 28 Marrow 15 1/27 (4) (19–55) 26 matched 2 mismatched Uberti52a 44 Tacro 43 PBSC 34 6/41 (13) (20–60) Tacro/MTX 4 43 matched 4 mismatched Przepiorka53b 34 Tacro/MTX ± MP 33 Marrow 44 16 0/85 (0) 39 CsA/MTX ± MP 52 PBSC 41 45 (18–59) Non-randomized 85 matched P= 0.02 Hiraoka50 Not mentioned Tacro/MTX or steroid 32 Marrow 12.5 Not mentioned CsA/MTX or steroid 30 40 Randomized P Ͻ 0.05 Ratanatharathorn54c 40 Tacro/MTX 165 Marrow 31.9 117/152 (54) (16–63) CsA/MTX 164 329 matched 44.4 Randomized P = 0.01

MTX, unless indicated otherwise, methotrexate was given i.v. at the dose of 15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6 and 11. aMini-MTX is methotrexate 5 mg/m2 given i.v. on days 1, 3, 6 and 11. bDifferent dose schedules of methotrexate were used: mini-MTX, MTX, or methotrexate or 10 mg/m2 on days 1, 3 and 6. cThis study was recently updated with a follow-up of at least 2 years, the manuscript is in preparation. Tacrolimus for the prevention of GVHD P Jacobson et al 220 Table 2 Transplants using unrelated donor and tacrolimus for acute GVHD prophylaxis

Ref. Median age in years GVHD prophylaxis n Source of stem cells % Acute GVHD TBI/Non-TBI (range) grade II–IV preparative regimen (% TBI)

Nash55 41 Tacro/MTX 43 Marrow 42 32/11 (74) (15–54) 42 matched 1 mismatched Przepiorka56 36 Tacro/mini-MTX 30 Marrow 34 19/11 (63) (22–49) 22 matched 8 mismatched Devine57 31 Tacro/mini-MTX 26 Marrow 50 25/1 (96) (19–52) 16 matched 10 mismatched Hiraoka50 Not mentioned Tacro/MTX or steroid 32a Marrow 20.6 Not mentioned CsA/MTX or steroid 34b 51.4 Randomized P Ͻ 0.05 Nash58 Not mentioned Tacro/MTX 90 Marrow 56 Not mentioned CsA/MTX 90 180 matched 74 Randomized P = 0.0002

aIncluded four patients who received a non-sibling related donor marrow. bIncluded two patients who received a non-sibling related donor marrow.

trexate may not correlate with the rate of acute GVHD.51 sporine. The reason for the survival disadvantage in this Thus, it is possible that an attenuated dose of methotrexate subset of patients is unclear. Although several subsequent may indeed preserve the immunosuppressive activity while reports which included patients with advanced malignancy minimizing the mucosal toxicity. This strategy has been have reported excellent results, its use in patients with used effectively in several studies which included both advanced malignancy should be cautioned. related and unrelated donor transplantation.53,56,57 Second, what should be the starting dose of tacrolimus? The i.v. dose of tacrolimus employed in these studies ranged from Adverse effects 0.03 to 0.05 mg/kg/day.32,33,50–58 Tacrolimus was administered by continuous infusion followed by oral adminis- The major adverse effects associated with tacrolimus con- tration at four times the intravenous dose when patients sist of nephrotoxicity,32,33,51,55,60,61 neurotoxicity,62–68 hyp- were able to tolerate oral intake. It is clear that even at a erglycemia69–72 and hypertension.73,74 Other less prevalent starting dose of 0.03 mg/kg/day, patients were unable to adverse effects include infectious complications,75–79 tolerate tacrolimus for more than several weeks because of lymphoproliferative disorders,80–83 microangiopathic hemo- nephrotoxicity. Przepiorka et al56 reported a series of lytic anemia,84 electrolyte abnormalities such as hyperkale- patients who received a starting dose of 0.03 mg/kg/day, mia,85 hypomagnesemia,86 and hypercholesterolemia.36,87 the median last i.v. dose of tacrolimus was 53%, and the Unlike cyclosporine, tacrolimus rarely causes hirsutism, median oral dose at day 100 was 41% of the scheduled gingival hyperplasia, or coarsening of facial features.88,89 dose. This suggests that the starting i.v. dose of tacrolimus The incidence of adverse events in stem cell transplant should not exceed 0.03 mg/kg/day and serum creatinine recipients is probably different from patients who had kid- must be closely monitored. Third, should we adopt a tacrol- ney or liver transplantation. This is due to the differences imus whole blood level between 10–30 ng/ml as employed in dose schedule of tacrolimus employed in these clinical in many of these studies? An analysis to correlate the whole scenarios, concomitant use of other immunosuppressive blood level of tacrolimus with the incidence of acute agents, the presence of pre-existing organ dysfunction and GVHD and nephrotoxicity has been reported.59 There was toxicity from tumor-ablative regimens. Therefore, the pat- no relationship between the whole blood level of tacrolimus tern of adverse events seen in solid organ transplant recipi- and the rate of acute GVHD. On the other hand, nephrotox- ents may not be applicable to bone marrow transplant icity significantly increased when the whole blood levels patients. exceeded 20 ng/ml. This study suggests that the whole blood level of tacrolimus should be kept at 10–20 ng/ml. Renal effects Fourth, can tacrolimus be used safely in patients with advanced malignancies? In the multicenter randomized Like cyclosporine, tacrolimus is a nephrotoxic agent. Sev- study comparing tacrolimus with cyclosporine in sibling eral mechanisms of tacrolimus nephrotoxicity have been marrow transplant recipients, patients with advanced malig- identified. Tacrolimus may lower the concentration of renin nancy randomized to the tacrolimus arm had a significantly and aldosterone.90 It also increases renal vascular resist- poorer survival compared to patients who received cyclo- ance, reduces glomerular filtration rate and renal plasma Tacrolimus for the prevention of GVHD P Jacobson et al 221 flow, possibly by inducing the synthesis of endothelins incidence of severe headaches or burning paresthesia was which are renal vasoconstrictor peptides,91,92 and the vaso- 61% and some patients required narcotics for pain control.33 constrictor thromboxane A2.93 These mechanisms may act These severe neurologic symptoms occurred while patients simultaneously in a given clinical situation. However, cen- were receiving intravenous infusions and symptoms tral to these physiologic derangements may be the binding improved or resolved after decreasing the infusion rate or of calcineurin in the kidney by the drug–immunophilin switching to the oral route. Reversible cerebral blindness complex, which is shared by both cyclosporine and and posterior leukoencephalopathy were also reported with tacrolimus.94 both cyclosporine and tacrolimus.68,103 Factors that may be In several large clinical trials, nephrotoxicity was defined associated with neurotoxicity are hypocholesterolemia, either as a doubling of serum creatinine to twice the base- hypertension, hypomagnesemia, nephrotoxicity and high line or as a serum creatinine Ͼ2.0 mg/dl. In these studies, blood levels of tacrolimus.68,106–109 the incidence of nephrotoxicity ranged from 32–92.6% in 32,33,51 related donor transplants and 63–88% in unrelated Hypertension donor transplants.55–57 Several factors contribute to the development of hyperten- TTP/HUS sion seen with the administration of tacrolimus. These factors include intrinsic renal damage caused by the drug, Hemolytic uremic syndrome and thrombotic thrombocyto- increased vasomotor tone, increased intravascular volume penic purpura during tacrolimus therapy has been reported and concomitant use of corticosteroids.110,111 Hypertension following bone marrow transplantation.95,96 In contrast, tac- requiring treatment ranged between 21–63% in related and rolimus has also been used as a successful alternative in unrelated donor transplants.32,33,51,55,56 The wide range seen patients with cyclosporine-induced hemolytic uremic in these studies may be due to the many confounding vari- syndrome.97,98 ables such as steroids which contribute to the incidence of hypertension. Hyperglycemia The diabetogenic effects of tacrolimus most likely result Drug interactions from the combined effects of inhibition of insulin secretion99 and peripheral insulin resistance.100 In one ani- Tacrolimus has been shown to act as an inhibitor of cytoch- mal model, administration of tacrolimus at 10 mg/kg/day rome-P450 drug metabolism, making many drug interac- orally for 2 weeks caused a time-dependent suppression of tions possible.112–114 Most of the drug interactions postu- insulin gene transcription in pancreatic beta cells due to lated have been based on in vitro data and little information inhibition of calcineurin.101 Insulin mRNA transcription exists from human trials.115–117 There is a high likelihood and insulin production returned to normal when the drug of drug interaction between tacrolimus and other agents was discontinued, indicating that the adverse effect of tac- administered concomitantly. Drug interactions with tacrol- rolimus on the pancreas is reversible.101 Clinically, it is imus that are known to occur or for which a strong possi- unclear whether the hyperglycemia associated with tacrol- bility for interaction exists are listed in Table 3. Agents imus is dose-dependent.72,88 In a study using tacrolimus known to induce or inhibit the P450 enzyme system should alone for GVHD prophylaxis, the incidence of hyperglyce- be administered with caution to patients receiving tacrol- mia requiring treatment during the first 6 months was 41%.32 Hyperglycemia requiring insulin treatment occurred 27,30,115,116,120–129 in 5% of patients.56 Many patients who developed GVHD Table 3 Potential drug interactions with tacrolimus were treated with corticosteroids, thus the additive effect of Drugs that may increase tacrolimus concentrations corticosteroids on hyperglycemia cannot be assessed. Other Cimetidinea,g Fluconazolea,b Nifedipinec,e confounding factors may also contribute to hyperglycemia Clarithromycina Glipizidea Omeprazolea,c such as parenteral nutrition and pancreatitis. Clotrimazoleb Itraconazolea,b Oral contraceptivesa,c Danazola,b Ketoconazolea,b,c Prednisolonea,f,c Diltiazema,c,g Methylprednisolonec,f Quinidinec Neurotoxicity Erythromycina,b Metoclopromidea Sulindacc Ergotaminec Nicardipinea Verapamila,c,g The clinical spectrum of neurotoxicity of cyclosporine and Famotidinea tacrolimus is very similar, ranging from mild symptoms of Drugs that may decrease tacrolimus concentrations tremor and paresthesia to severe manifestations such as c a 33,47,48,68,102–104 Antacids Phenytoin cortical blindness and seizures. The simi- Carbamazepinea Rifabutin larities in the neurologic manifestations of these two agents, Phenobarbitala,d Rifampina,b suggest a common mechanism of neurotoxicity, probably mediated through the interaction of drug–immunophilin aPossible interaction, documented human interaction with cyclosporine. complex with calcineurin.105 Other neurological side– bDocumented tacrolimus interaction in humans. effects in marrow transplant recipients include headaches, cPossible interaction, based on in vitro tacrolimus data. dUnlikely interaction, based on in vitro tacrolimus data. tremor, feeling of warmth, aphasia, flaccid paralysis, par- eUnlikely interaction, based on cyclosporine human data. esthesia of the extremities, insomnia, somnolence, rigidity fUnlikely interaction, based on tacrolimus human data. of the limbs and nystagmus.33,47,48,55,102 In one study, the gDocumented tacrolimus interaction in the animal model. Tacrolimus for the prevention of GVHD P Jacobson et al 222 imus, and close therapeutic drug monitoring should be 2 Nash RA, Pepe MS, Storb R et al. Acute graft-versus-host performed. disease: analysis of risk factors after allogeneic marrow trans- Pharmacokinetic studies in BMT patients who received plantation and prophylaxis with cyclosporine and methotrex- tacrolimus alone or in combination with methylpredniso- ate. Blood 1992; 80: 1838–1845. lone or methotrexate showed no difference in clearance of 3 Storb R, Leisenring W, Deeg HJ et al. Long-term follow-up 33 of a randomized trial of graft-versus-host disease prevention tacrolimus. On the other hand, there was a concern by methotrexate/cyclosporine vs methotrexate alone in regarding the potential of delayed clearance of methotrexate patients given marrow grafts for severe aplastic anemia. Blood by tacrolimus via mechanisms similar to another macrolide- 1994; 83: 2749–2750 (letter). like compound, pristinamycin.118 This issue was addressed 4 Storb R, Deeg HJ, Pepe M et al. Methotrexate and cyclosporin a study of 80 BMT recipients participating in a ran- ine versus cyclosporine alone for prophylaxis of graft-versus- domized study comparing tacrolimus/methotrexate and host disease in patients given HLA-identical marrow grafts for cyclosporine/methotrexate. This study did not find a sig- leukemia: long-term follow-up of a controlled trial. Blood nificant alteration in methotrexate clearance by tacrol- 1989; 73: 1729–1734. imus.119 Fluconazole is another common agent given con- 5 Chao NJ, Schmidt GM, Niland JC et al. Cyclosporine, metho- comitantly with tacrolimus. Osowski et al120 investigated trexate, and prednisone compared with cyclosporine and prednisone for prophylaxis of acute graft-versus-host disease. the interaction between daily intravenous fluconazole dose New Engl J Med 1993; 329: 1225–1230. of 400 mg/kg and cyclosporine or tacrolimus in allogeneic 6 von Bueltzingsloewen A, Belanger R, Perreault C et al. Acute BMT patients. They reported that the clearances of cyclos- graft-versus-host disease prophylaxis with methotrexate and porine and tacrolimus were reduced by 21% and 16%, cyclosporine after busulfan and cyclophosphamide in patients respectively. The authors felt that the alterations of tacrol- with hematologic malignancies. Blood 1993; 81: 849–855. imus clearance were not clinically significant. However, 7 Storb R, Deeg HJ, Farewell V et al. Marrow transplantation concomitant administration of fluconazole and tacrolimus for severe aplastic anemia: methotrexate alone compared with in solid organ transplant recipients had resulted in acute a combination of methotrexate and cyclosporine for preven- renal toxicity.121,122 The difference might have been that tion of acute graft-versus-host disease. Blood 1986; 68: solid organ transplant recipients received a higher dose of 119–125. 8 Storb R, Deeg HJ, Whitehead J et al. Methotrexate and cyclos- tacrolimus. The potential drug interaction of tacrolimus porine compared with cyclosporine alone for prophylaxis of underscores the needs for vigilant monitoring of the blood acute graft-versus-host disease after marrow transplantation levels in BMT patients, whose clinical complexity often for leukemia. New Engl J Med 1986; 314: 729–735. demands the concomitant use of multiple pharmacologic 9 Storb R, Pepe M, Deeg HJ et al. Long-term follow-up of a agents. controlled trial comparing a combination of methotrexate plus cyclosporine with cyclosporine alone for prophylaxis of graft- versus-host disease in patients administered HLA-identical Conclusion marrow grafts for leukemia. Blood 1992; 80: 560–561 (letter). 10 Kino T, Hatanaka H, Hashimoto M et al. FK-506, a novel Tacrolimus is a new macrolide immunosuppressant with a immunosuppressant isolated from a Streptomyces. I. Fermen- mechanism of action similar to that of cyclosporine. Tacrol- tation, isolation, and physicochemical and biological charac- imus has been shown to be effective in the prevention of teristics. J Antibiot (Tokyo) 1987; 40: 1249–1255. acute GVHD. Common adverse effects of tacrolimus, like 11 Klintmalm GB. FK506: an update. Clin Transplant 1994; 8: cyclosporine, are nephrotoxicity, neurotoxicity, hyperglyce- 207–210. 12 Warty V, Diven W, Cadoff E et al. FK506: a novel immuno- mia and hypertension. However, tacrolimus rarely causes hir- suppressive agent. Characteristics of binding and uptake by sutism or gingival hyperplasia. Three large randomized trials human lymphocytes. Transplantation 1988; 46: 453–455. have been completed, comparing tacrolimus to cyclosporine 13 Yoshimura N, Matsui S, Hamashima T et al. A new immuno- for the prevention of GVHD in matched sibling donor trans- suppressive agent, FK506, inhibits the expression of alloan- plantation and matched unrelated donor transplantation.50,54,58 tigen-activated suppressor cells, as well as the induction of All three trials showed the superiority of tacrolimus over alloreactivity. Transplant Proc 1989; 21: 1045–1047. cyclosporine in the prevention of grade II–IV acute GVHD. 14 Thomas J, Matthews C, Carroll R et al. The immunosuppres- In the trials which included only non-advanced malignancies, sive action of FK506. In vitro induction of allogeneic unre- the survivals were similar. Several single institution trials of sponsiveness in human CTL precursors. Transplantation tacrolimus, which include many patients with advanced dis- 1990; 49: 390–396. 15 Yoshimura N, Matsui S, Hamashima T et al. Effect of a new ease both in sibling and unrelated donor transplantation, have 32,33,51,52,56,57 immunosuppressive agent, FK506, on human lymphocyte reported excellent survivals. responses in vitro. II. Inhibition of the production of IL-2 and The clinical application of tacrolimus for the treatment gamma-IFN, but not B cell-stimulating factor 2. Transplan- and prevention of GVHD will continue to evolve. Future tation 1989; 47: 356–359. studies of this agent in combination with other immunosup- 16 Kino T, Hatanaka H, Miyata S et al. FK-506, a novel immuno- pressants for GVHD prevention may further improve the suppressant isolated from a Streptomyces. II. Immunosuppres- outcome of allogeneic bone marrow recipients. sive effect of FK-506 in vitro. 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