Correspondence. Lactoferrin for gut GVHD. Symptoms of gut graft-versus-host disease (GVHD) are frequent watery diarrhea accompanied by intolerable pain,.
Bone Marrow Transplantation (2001) 28, 1091–1092 2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt
Correspondence Lactoferrin for gut GVHD Symptoms of gut graft-versus-host disease (GVHD) are frequent watery diarrhea accompanied by intolerable pain, bloody stool, and paralytic ileus, and these symptoms have serious detrimental effects on both the physical and mental health of patients. It is very difficult to treat severe gut GVHD and we previously reported our experience using colostrum1 in treating this condition. However, the availability of colostrum may be limited and the quality varies. Lactoferrin is an attractive alternative that is abundant in colostrum, and we used recombinant human lactoferrin (Agennix, Houston, TX, USA) for the treatment of gut GVHD refractory to conventional immunosuppressive therapy. Here, we report the dosage and a typical case study. Lactoferrin was administered orally three times a day for 5 days or more and the dose was set according to the patient’s body weight (300 mg/day: −20 kg, 600 mg/day: 20–40 kg, 750 mg/day: +40 kg). No adverse reactions were noted and four out of seven patients with severe gut GVHD showed clinical improvement after lactoferrin administration (Table 1). Rectal biopsies were performed and histological findings were compatible with enteric GVHD in all patients. CMV genome was negative by FISH. Rotaviruses and adenoviruses were not detected in the stool tested by ELISA. One typical case (UPN 204) is reported. The patient was diagnosed with acute lymphoblastic leukemia (ALL) at the age of 4 years and he received an unrelated two antigen HLA-mismatched cord blood transplant in third complete remission at the age of 11. Conditioning consisted of TBI (12 Gy), cytosine arabinoside (12 g/m2) and LPAM (140 mg/m2). FK506 and methylprednisolone (mPSL) were used for GVHD prophylaxis. Ganciclovir was
Lactoferrin
Colostrum
Volume of stool (ml/day)
UCBSCT
MTX Pulse
2000 FK506
CsA Rectal biopsy
Rectal biopsy
mPSL
1000
0
administered from day −8 to day −1 because the patient was CMV-seropositive. FK506 was switched to cyclosporin A on day 18 post transplant because of a seizure suspected to be an adverse reaction to FK506. Engraftment was similar to that seen in other cases of cord blood stem cell transplantation. Neutrophils rose to 0.5 × 109/l on day 25 and the platelet count to 20 × 109/l on day 70. Reticulocytes reached 1% on day 36. Complete chimerism was confirmed by HLA typing on day 30. The patient developed grade III acute GVHD, and a systemic rash appeared on day 21 followed by watery diarrhea accompanied by severe pain. A rectal biopsy was performed twice and histological findings were compatible with enteric GVHD. CMV was not detected by in situ hybridization. The systemic rash disappeared, but symptoms of gut GVHD persisted in spite of high-dose mPSL (pulse therapy), methotrexate and colostrum. Therefore, we decided to use lactoferrin combined with pulsed systemic immunosuppressive therapy and methotrexate. Lactoferrin was administered orally 750 mg/day (three times a day) for 4 weeks. Symptoms of gut GVHD disappeared soon after lactoferrin therapy was started, as shown in Figure 1. Lactoferrin is present in colostrum. It has been reported to be a 80-kDa cationinc protein hypothesized to have some roles in iron metabolism and many other functions such as an anti-inflammatory effect, anti-microbial effect and immunomodulative ability.2 It has been reported that lactoferrin inhibits mitogen- and alloantigen-induced human lymphocyte proliferation. We anticipate that lactoferrin can be used as an alternative to colostrum and on the basis of our findings in the present preliminary trial we suggest the potential benefit of lactoferrin for severe gut GVHD. The efficacy of lactoferrin therapy for gut GVHD should be confirmed in more cases.
0
100
200 Days after UCBSCT
Figure 1 Clinical course of UPN 204.
300
Bone Marrow Transplantation
48 50 22 23 9 40 50
204 205 210 212 214 219 236
11 15 7 8 1 14 17
Age (years)
ALL AML ALL CAEBV CAMT CGD MDS
Disease
UCBSCT UBMT UBMT CD34BMT UBMT RBMT UBMT
SCT
TBI+CA+LPAM TBI+CY TBI+CA+CY TBI+VP16+CY TBI+TEPA BU+CY+ATG TBI+VP16+CY
Preconditioning
FK506+mPSL FK506+mPSL FK506+mPSL FK506 FK506+mPSL CSA FI506+mPSL
GVHD prophylaxis
Summary of seven cases undergoing lactoferrin therapy for gut GVHD
III IV III III III III III
Pulse, MTX Pulse, MTX Pulse, MTX Pulse, Pred Pulse, MTX Pulse Pulse, MTX
aGVHD Prior therapy of grade GVHD
750 mg 750 mg 600 mg 600 mg 300 mg 750 mg 750 mg
Pulse, MTX Pulse MTX Pulse, Pred Pulse, MTX Pred Pulse, MTX
Lactoferrin Immunosuppressive dose/day therapy with lactoferrin
2 3 3 2 4 4 2
0 1 0 2 4 0 2
PrePost lactoferrin lactoferrin
Stage of gut GVHD
+ + + − − + −
Effectiveness of lactoferrin
ALL = acute lymphoblastic leukemia; AML = acute myelogenous leukemia; CAEBV = chronic active Epstein–Barr virus infection; CAMT = congenital amegakaryocytic thrombocytopenia; CGD = congenital granulomatous disease; MDS = myelodysplastic syndrome; UCBSCT = HLA two loci mismatched cord blood stem cell transplantation; UBMT = HLA-matched BMT from unrelated donor; CD34BMT = BMT using CD34-positive cells from HLA-haploidentical father; RBMT = HLA-matched BMT from related donor; TBI = total body irradiation; CA = cytosine arabinoside; LPAM = l-phenylalanine mustard; CY = cyclophosphamide; VP16 = etoposide; TEPA = triethylene thiophosphoramaide; BU = busulfan; ATG = anti-thymocyte globulin; FK506 = tacrolimus; mPSL = methylprednisolone; CSA = cyclosporin A; Pulse = high-dose methylprednisolone therapy; MTX = methotrexate; Pred = prednisolone.
BW (kg)
UPN
Table 1
Correspondence
1092
M Inoue T Okamura M Yasui N Sakata K Yagi K Kawa Department of Pediatrics Osaka Medical Center and Research Institute for Maternal and Child Health Osaka 594-1101, Japan
References
1 Inoue M, Okamura T, Sawada A et al. Colostrum and severe gut GVHD. Bone Marrow Transplant 1998; 22: 402–403. 2 Levay PF, Viljoen M. Lactoferrin: a general review. Hematologica 1995; 80: 252–267.
