Established acute graft-versus-host disease (aGVHD) is commonly treated with cytotoxic agents or glucocorticoids,1,2 since studies using antithymocyte globulin (ATG) demonstrated no improvement over cyclosporine (CSP) or methylprednisolone (MP). In addition, ATG was associated with poor survival.3 Alemtuzumab targets the CD52 antigen and is effective in the prevention of aGVHD;4,5 however, no data have been reported on the use of this drug for the treatment of pre-existing aGVHD.
The induction of aGVHD requires host antigens to be presented to donor T cells by antigen-presenting cells, such as dendritic cells (DCs). Since CD52 has been reported to be expressed on monocyte-derived DCs,6 we reasoned that alemtuzumab might have a direct effect on DCs, in addition to any effects on donor T cells, not only for GVHD prevention but also for the treatment of aGVHD.
Case 1: A 53-year-old woman with high-risk, Philadelphia (Ph)-positive, chronic myeloid leukemia (CML) received fludarabine phosphate/total body irradiation (TBI) nonmyeloablative allografting7 from a HLA-identical sibling; aGVHD prophylaxis consisted of CSP, 3 mg/kg 24 h infusion (ci). The patient achieved full chimerism by day 35, followed by cytogenetic and molecular remission. On day 12, the patient developed skin grade II aGVHD. Subsequently, on day 23, GI and liver grade III aGVHD developed, combined with cytomegalovirus (CMV) reactivation. Ganciclovir plus high-dose MP, 3 mg/kg/day for 7 days, and CSP, 2 mg/kg/day ci, were given. CMV reactivation and skin aGVHD resolved; however, diarrhea and liver enzymes/bilirubin continued to increase. At 65 days post engraftment, liver biopsy confirmed aGVHD, CSP was stopped and alemtuzumab treatment was initiated. Levels of bilirubin (Figure 1) and liver enzymes were reduced in the 2 weeks following the last dose of alemtuzumab, and GI aGVHD resolved 1 week later. CMV-positive cells disappeared after 10 days of ganciclovir treatment. In the following weeks, the patient developed infectious complications, which resolved on treatment. However, renal failure, probably due to previous anti-CMV therapy, and, finally, cardiac failure occurred, causing death on day 106, without signs of GVHD.
Case 2: A 46-year-old man with high-risk CML received myeloablative allografting from an HLA-identical sibling. The patient was conditioned with cyclophosphamide, 60 mg/kg/day for 2 days, and TBI, 12 Gy (200 cGy twice daily for 3 days); aGVHD prophylaxis consisted of CSP, 3 mg/kg/day ci. Full chimerism was achieved by day 20, followed by complete cytogenetic remission. At 27 days post graft, GI grade III and liver grade IV aGVHD developed, and the patient received a 6-day course of MP, 2 mg/kg/day. However, liver aGVHD progressed under steroids; therefore, 2 days after MP, alemtuzumab was given. Before allografting, the B-cell subset and CD4+/CD8+ ratio were normal; resolution of aGVHD and bilirubin level (Figure 1) was accompanied by profound lymphopenia and a CD4+/CD8+ ratio of four, due to a disproportionate reduction of the CD8+ vs CD4+ subpopulation, indicating the pivotal role of alemtuzumab. Unfortunately, the patient developed CMV infection 48 h after the last dose of alemtuzumab. This failed to respond to ganciclovir, but resolved completely after a 16-day course of foscarnet. After a total of 73 mg alemtuzumab, complete regression of GI and liver grade III aGVHD was observed. The patient is now receiving maintenance therapy with mycophenolate mofetil, 1000 mg/day.
Case 3: A 44-year-old woman with relapsed, low-grade non-Hodgkin's lymphoma received fludarabine phosphate-melphalan reduced-dose allografting from an HLA-identical sibling; aGVHD prophylaxis consisted of methotrexate, 8 mg/m2 on days 1, 3, and 6, and CSP, 1 mg/kg/day ci. The patient developed skin and GI aGVHD on day 10, and the dose of CSP was increased to 2 mg/kg ci. Despite this, aGVHD worsened and liver grade III aGVHD developed. MP was started at a dose of 2 mg/kg/day for 6 days. During corticosteroid therapy, the level of bilirubin increased from 4.1 to 23.7 mg/dL in 4 days. Liver biopsy confirmed aGVHD; since bilirubin continued to progress for 6 days after MP, alemtuzumab was given. Alemtuzumab rapidly reduced bilirubin (Figure 1) and liver enzymes to normal levels; by day 3 after the first therapeutic dose, bilirubin was reduced to 14.4 mg/dl. The level of bilirubin increased (19.0 mg/dl) on day 4 and the patient was immediately treated with two additional 30 mg doses of alemtuzumab. This rapidly reduced the bilirubin level to 2.6 mg/dl. Skin aGVHD also disappeared, but GI grade I aGVHD still persists. As with Case 2, resolution of aGVHD was accompanied by profound panlymphopenia, reduction of CD8+ subsets, and disappearance of B lymphocytes, indicating the pivotal role of alemtuzumab.
All patients tolerated the alemtuzumab infusions with minimal side effects, which included rigor/chills (Case 3), fever (Case 1), and headache (Case 2). Neutropenia and thrombocytopenia were seen in two patients (Cases 1 and 2). In all patients, CMV reactivation was successfully treated with ganciclovir alone (Case 3) or ganciclovir plus foscarnet (Cases 1 and 2). In all the three patients, aGVHD (confirmed by liver biopsy in Cases 1 and 3, and bowel biopsy in Case 2) rapidly responded to alemtuzumab at all the remaining sites. All the patients maintained complete chimerism during and after alemtuzumab therapy.
The results presented demonstrate that alemtuzumab therapy was highly effective in treating steroid-resistant aGVHD at relatively low doses. In addition, it allowed complete chimerism to be maintained in all the three patients. These results will confirm the use of alemtuzumab as treatment may provide a further dimension to its well-established role as prophylactic for both acute and chronic GVHD.
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Carella, A., Beltrami, G., Scalzulli, P. et al. Alemtuzumab can successfully treat steroid-refractory acute graft-versus-host disease (aGVHD). Bone Marrow Transplant 33, 131–132 (2004). https://doi.org/10.1038/sj.bmt.1704322
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