Graft Versus Host Disease-Like Syndrome after Autologous Stem Cell Transplantation in CLL Patients Treated with a TBI/Cy/Alemtuzumab (CAMPATH-1H) High-Dose Regimen.

Introduction: A high incidence of unexplained skin rashes after an alemtuzumab containing high-dose regimen led us to retrospectively review CLL patients who underwent autografting within the CLL3C/CLL3 trials of the German CLL Study Group (GCLLSG) at a single center (University of Ulm).

Patients and Methods: CLL patients who received an autologous SCT after high-dose regimens with TBI (12Gy) / Cyclophosphamide (120mg/kg) without (CLL3: TBI/Cy) or with alemtuzumab (103mg i.v.) (CLL3C: TBI/Cy/A) between 2000 and 2004. Before SCT the patients received cytoreduction with FC and PBSC graft mobilization with Dexa-BEAM + G-CSF.

Results: 27 CLL patients received an autologous SCT after high-dose regimens with TBI/CY (n=11, age 34–61) or TBI/Cy/A (n=16, age 34–65). A mean of 6.0 (±2.8) (TBI/Cy) and 7.6 (±6.1) (TBI/Cy/A) x10-6 CD34+ cells/kg were transfused. At a median follow up of 24 months, overall survival was not different in the two groups (TBI/Cy: 91%; TBI/Cy/A: 81%). Twelve of 16 (75%) patients (TBI/Cy/A) developed a skin rash 43–601 days after transplantation (not including immediate alemtuzumab side effects) and 7 (44%) were classified as acute GvHD (skin grade 1–3). Concurrent symptoms included conjunctivitis (n=4), sicca syndrome(n=5), and cholestasis (n=4). The incidence of GvHD among patients alive at 1 year was 58% (TBI/Cy/A) vs. 0% (TBI/Cy) (log rank p=0.0048). On skin biopsy, the findings were compatible with GvHD grade 1–2 in 5/5 patients. All patients with GvHD were treated with steroids and in two patients GvHD was severe enough to lead to further immunosuppression with cyclosporine, MMF or FK506. In 3 patients signs and symptoms resolved and 4 patients improved but continued to have mild skin rashes and symptoms. Immune reconstitution showed that the CD4/CD8 ratio was more than 12 times higher in the TBI/Cy/A group (8.0 vs 0.6). When comparing the patients with GvHD with patients not developing a skin rash in the TBI/Cy/A group, the difference was statistically significant (ratio 20.3 (95%CI 4.8–35.7) vs 1 (95%CI0.7–1.3), Mann-Whitney: p=0.00001). The high ratio was due to an extreme depletion of CD8 positive T cells.

Conclusion: The incorporation of alemtuzumab into the high-dose regimen prior to autologous SCT in CLL led to a high incidence of a GvHD-like syndrome primarily of the skin. The remarkable incidence of GvHD went along with the severe depletion of CD8+ T-cells leading to an abnormally high CD4/CD8 ratio. The further investigation of the underlying mechanisms may lead to a better understanding of the development of GvHD and autoimmune disease and serve as a model system of these disorders.