GvHD Prophylaxis with Everolimus and Mycophenolate in Allogeneic Hematopoietic Cell Transplantation - A Phase I/II Study.

Abstract 4642

Next to the control of malignant disease, tolerance induction of the grafted cells remain to be a critical issue for longterm survivors after allogeneic hematopoietic cell transplantation (HCT). Regulatory T cells (Tregs) are believed to be involved in the process of tolerance induction to solid organ grafts and in the regulation of alloreactivity, e.g. graft versus host disease (GvHD) and graft versus leukemia effect (GvL), after allogeneic HCT. Since GvHD causes substantial morbidity, medication with calcineurin inhibitors (CI) like cyclosporine are established prophylactic measures for the prevention of GvHD after HCT. Next to the substantial renal toxicity of CI, tolerance induction might be hampered in HCT patients due to deteriorated Treg function. In contrast, data from in vitro and animal experiments suggest that inhibition of the mammalian target of rapamycin (mTOR) has not only an antiproliferative effect on many malignant cell lines but also results in an inhibition of proliferation of alloreactive T cells with sustained Treg function in a murine HCT model. Therefore we initiated a phase I/II, monocenter trial using everolimus and mycophenolate sodium (MMF-Na) as GvHD prophylaxis in patients undergoing allogeneic HCT with peripheral stem cell (PBSC) grafts after conditioning with fludarabine, melphalan, and BCNU (FBM). No additional T cell depleting agents were used for conditioning/GvHD prophylaxis. Enrolment was started in april 2008, and up to august 2009 10 patients were included (median age: 50.7 years, range: 26-64). The diagnoses included de novo AML (n=3), sAML (n=4), RAEB II (n=1), CML (n=1), T-PLL (n=1). 6/10 patients were regarded as high risk (not in CR1) for early relapse. PBSC grafts were obtained from unrelated (n=5) and related (n=5) HLA-matched donors. With no graft failures, engraftment kinetics for myeloid cells were normal, and reconstitution of the T cell compartment reached median cell counts of 251 CD4+ cells/μl and 163 CD8+ cells/μl at day +30. No grade IV/V toxicities (according to CTC criteria) were observed due to the study medication. After a median follow-up of 6 month two patients have died. The causes were acute GvHD, refractory to several lines of treatment, in a patient with CML, and severe pulmonary toxicity/BOOP in a patient with sAML. Out of 9 patients reaching CR after HCT, only one high risk patient relapsed after 6 month. In total 6 patients are alive and show complete donor chimerism for time periods of 1-14 months post transplant. The observed early recovery of T cell immunity correlated in 8/10 patients with an early brief period of acute GvHD, with 4 patients experiencing grade III/IV severities. Most of the cases could be controlled with steroids alone. Chronic GvHD could be observed in 6/7 patients, with mild to moderate forms in 5 cases, mainly involving skin, mucosa and liver. Interestingly, while early tapering of MMF-Na did not cause any problems, reduction of everolimus earlier as 6 month after HCT resulted in an induction of GvHD symptoms. Although viral reactivation (CMV, HHV6) did occur in patients receiving additional immunosuppression with steroids, no severe bacterial or fungal infections were observed even in cases with prolonged everolimus treatment. In conclusion, GvHD prophylaxis with everolimus and MMF-Na is feasible but results in an increased frequency of mild to moderate chronic GvHD. Since this sustained mild alloreactivity might reduce the risk of relapse, this GvHD prophylaxis could well be suited for patients undergoing HCT with advanced or uncontrolled malignant disease.