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 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.
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