GVHD leads to increased morbidity and mortality after allogeneic hematopoietic SCT (HCT).1 Compared with myeloablative regimens (MARs), nonmyeloablative conditioning regimens do not appear to decrease the rate of serious GVHD.2 In steroid-resistant patients, various immunosuppressive agents including antibodies against IL-2 and TNF have been attempted.3, 4, 5 Outcome is very poor in patients who do not respond second-line treatment, in particular, if they have gut GVHD. Non-relapse mortality was 71% at 1-year post-HCT in patients with steroid-refractory gut GVHD.6 Survival rate decreases to 16% in adults not responding to steroids within 2 weeks6 or 0% in adults and children not responding to a combination of anti-IL-2 and anti-TNF.3, 4 A second HCT from another donor could improve gut GVHD in mice.7 We performed an HCT from a second HLA-matched sibling for treatment of severe acute gut GVHD in a patient in whom all other therapeutic approaches had been exhausted.
A 31-year-old man with wt loss and bone pain in his legs, presented with a WBC count 6.7 × 109/l, 14% blasts, hemoglobin 9.8 g per 100 ml, and plt count 154 000 × 109/l. A BM biopsy revealed 4+ reticulin fibrosis and 16% myeloblasts, consistent with advanced stage primary myelofibrosis. He was initially treated with lenalidomide and then a panhistone deacetylase inhibitor (LBH589). He received an HCT from his 22-year-old brother after treatment with melphalan (140 mg/m2) and fludarabine (120 mg/m2). He was treated with tacrolimus (0.03 mg/kg/day i.v. continuous infusion), initiated day −2 and mycophenolate mofetil (1 g i.v. b.i.d.) initiated day 0. He received G-CSF, acyclovir, fluconazole and levofloxacin. On day +7, he developed clinical grade III gut GVHD (1.5–2 l/d of diarrhea). Four days after initiating treatment with methylprednisolone (1 mg/kg i.v. b.i.d.) and total parenteral nutrition, his symptoms resolved. Neutrophil and plt engraftment occurred on days +10 and +42, respectively. Chimerism analysis revealed 100% donor-derived cells on day +14. Steroids were tapered off within 4 months. At 5 months post transplant, he developed recurrent gut GVHD with severe abdominal pain and 1.5 l of diarrhea per day. Colonic biopsy revealed extensive mucosal ulceration and complete crypt loss, consistent with severe (grade IV) acute GVHD (Figure 1). High-dose therapy with methylprednisolone, infliximab (anti-TNF) and daclizumab (anti-IL-2) did not improve GVHD. Severe gut GVHD persisted despite sequential treatment with extracorporeal photopheresis, rituximab, CY and pentostatin. A second HCT from another donor for treatment of steroid-resistant GVHD was proposed to him and his family. Although this approach had not been used for this purpose, previously, he offered his consent for the procedure, and our institutional ethical committee approved the second transplant. He received a second transplant from his HLA-identical youngest brother (13 years old) 3 months after recurrence of gut GVHD. The conditioning regimen consisted of CY (60 mg/kg on days −7 and −6) and BU (0.8 mg/kg for 14 doses from days −5 to −2). The planned 15th and 16th doses of BU were not given to prevent further delay of stem cell infusion. A total of 7 × 106 CD34+ stem cells and 627.9 × 106 CD3+ cells were infused 36 h after the final dose of BU. GVHD prophylaxis was initiated with tacrolimus (day −2) and MTX (day 1 at 15 mg/m2). The remaining planned doses of MTX on days 3, 6, 11 were not given secondary to severe hepatotoxicity. MTX was replaced with mycophenolate mofetil (1 g i.v. b.i.d.) and methylprednisolone (1 mg/kg). He developed respiratory failure mostly secondary to vol overload and was intubated on day 4. His total bilirubin increased to 20 mg per 100 ml, despite supportive measures to prevent expected hepatotoxicity (for example, i.v. administration of N-acetyl-cysteine and deferoxamine) followed by renal failure requiring hemodialysis and an ileus. On day 18, the WBC and ANC reached 1.6 × 109/l and 1.48 × 109/l, respectively. Chimerism analysis revealed 99.6% of the second donor-derived cells in the peripheral blood. Ileus resolved, and total parenteral nutrition was replaced with oral-duodenal tube feedings. Colonic biopsy showed numerous glands with architectural variation, consistent with regeneration (Figure 2). The serum total bilirubin peaked at 50 mg per 100 ml, despite adjustment of medications, antithrombin III and low-dose heparin administration. A transvenous intrahepatic portal shunt was placed for management of suspected sinusoidal obstruction syndrome. A liver biopsy was performed and revealed severe biliary stasis and iron overload with no evidence of GVHD or sinusoidal obstruction. He expired with multiorgan failure on day 35.
This case report shows that severe gut GVHD can improve after a second HCT from a different donor. However, our patient died with toxicity most like caused by the second conditioning regimen. The optimal conditioning regimen before a second HCT for this indication is unknown because it has been done for graft failure or relapse. First donor lymphocytes could persist and cause severe acute GVHD even after a second HCT from a different donor.8 MAR have the potential advantage of eliminating pathogenic lymphocytes from the first donor, and T cells from the second donor might also help eliminate lymphocytes from the first donor. Some patients can tolerate myeloablative conditioning regimens before a second transplant for treatment of recurrent malignancy,9 but the risk of regimen-related toxicity is very high, especially in patients who have severe GVHD complicated by poor nutrition. As an alternative, nonmyeloablative conditioning regimens have also been used successfully for second HCT in patients who rejected a prior allograft from a different donor.10 We used a MAR in our patient, because he had no active infection and had a good performance status.
With the use of better supportive measures, a second HCT appears to be more feasible because patients can be kept in a better performance status without invasive infections for a longer time. Our results encourage early consideration of a second HCT from a different donor in patients with severe resistant gut GVHD. Further work is needed to develop a conditioning regimen that could enable reliable second engraftment without causing life-threatening toxicity in patients who have already debilitation caused by severe GVHD.
Carnevale-Schianca F, Leisenring W, Martin PJ, Furlong T, Schoch G, Anasetti C et al. Longitudinal assessment of morbidity and acute graft-versus-host disease after allogeneic hematopoietic cell transplantation: retrospective analysis of a multicenter phase III study. Biol Blood Marrow Transplant 2009; 15: 749–756.
Sala-Torra O, Martin PJ, Storer B, Traina F, Sorror ML, Storb R et al. Serious acute or chronic graft-versus-host disease after hematopoietic cell transplantation: a comparison of myeloablative and nonmyeloablative conditioning regimens. Bone Marrow Transplant 2008; 41: 887–893.
Wolff D, Roessler V, Steiner B, Wilhelm S, Weirich V, Brenmoehl J et al. Treatment of steroid-resistant acute graft-versus-host disease with daclizumab and etanercept. Bone Marrow Transplant 2005; 35: 1003–1010.
Rao K, Rao A, Karlsson H, Jagani M, Veys P, Amrolia PJ . Improved survival and preserved antiviral responses after combination therapy with daclizumab and infliximab in steroid-refractory graft-versus-host disease. J Pediatr Hematol Oncol 2009; 31: 456–461.
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Taniguchi Y, Yoshihara S, Hoshida Y, Inoue T, Fujioka T, Ikegame K et al. Recovery from established graft-vs-host disease achieved by bone marrow transplantation from a third-party allogeneic donor. Exp Hematol 2008; 36: 1216–1225.
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We thank the family of the late Adolfo Garcia for permission to report this case. We also thank the following individuals for their great contribution that made possible the second transplantation for the first time: Julie Neal, RN; Alan Roberts, MD; James Wynn, MD; Roger Vega, MD; Kavita Natarajan, MD; Lloyd Cook, MD; Adil Degani, MD; Sandra Helman, PhD; Emily Moore, RN; Helen Fain, RN; Richard Sattin, MD.
The authors declare no conflict of interest.
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Ustun, C., Jillella, A., Shah, R. et al. Second allo-SCT from a different donor can improve severe steroid-resistant gut GVHD. Bone Marrow Transplant 45, 1658–1660 (2010) doi:10.1038/bmt.2010.17
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