Everolimus and Mycophenolate as GvHD Prophylaxis Results In Improved Control of Advanced Disease and Reduced Bacterial and Fungal Infectious Complications After Allogeneic Stem Cell Transplantation

Abstract 1264

Tolerance induction together with sustained disease control remain to be critical for longterm survivors after allogeneic hematopoietic cell transplantation (HCT). Regulatory T cells (Tregs) are involved in the regulation of graft versus host disease (GvHD) and graft versus leukemia effect (GvL). Although calcineurin inhibitors are frequently being used for the prevention of GvHD, tolerance induction might be hampered in HCT patients due to deteriorated Treg function. Data from animal models of HCT suggest that inhibition of the mammalian target of rapamycin (mTOR) results not only in suppressed T cell alloreactivity but also in sustained Treg function. On the other hand severe reduction of T cell alloreactivity might result in diminished control of especially advanced malignant disease. To explore the clinical efficacy of a calcineurin-free GvHD prophylaxis regimen, 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 reduced toxicity and standard conditioning. 28 patients were included (median age: 49,2 years, range: 21–65). The diagnoses were: AML/MDS (n=16), ALL (n=3), CML/MPS (n=3), T-PLL (n=1), NHL/CLL (n=6). At the time of transplantation 22/28 (78%) patients were at high risk (not in CR1/CP, untreated) for early relapse. Conditioning included fludarabin based reduced intensity (n=24) or standard regimens containing busulfan (n=2) or clofarabine (n=2). Four CR1 patients received additional alemtuzumab (total 10mg) for GvHD prophylaxis. PBSC grafts were obtained from unrelated (n=20) and related (n=8) HLA-matched donors. No graft failure occurred. Engraftment kinetics for myeloid cells were normal, patients without alemtuzumab showed rapid reconstitution of the T cell compartment with median cell counts of >200 CD4⁺ cells/μl at day +30 together with complete donor chimerism in 15/18 evaluable patients. No grade IV/V toxicities (according to CTC criteria) were observed due to the study medication. After a median follow up of 9 months, 3 relapses of 24 patients with CR after HCT (12,5%) occurred, of those one AML patient could be salvaged with withdrawal of immunosuppression. Nine patients have died. The causes were underlying malignant disease (n=2), GvHD (n=2), viral infections (n=3 with two cases of HHV6 associated encephalitis), post-surgery thrombembolism (n=1), and one unknown. Treatment related mortality after 100 days is 14,2%, after 1 year 21,4%. Due to the early recovery of T cell immunity mild forms of acute skin GvHD were common early after reconsitution, while acute GvHD Grade III-IV could be observed in 8/26 patients. Chronic GvHD occurred in 15/22 patients (68%) with moderate and severe forms in n=10 and n=3 patients, respectively. Cytomegalovirus (CMV) reactivation could be seen in 5/20 patients at risk, while no CMV disease developed. Importantly, in the first year after HCT no severe bacterial or fungal infections were observed even in cases with prolonged everolimus treatment. The whole cohort experienced a median overall survival of 20 months, median progression free survival was 19 months. In conclusion, GvHD prophylaxis with everolimus and MMF-Na is feasible but results in an increased frequency of moderate chronic GvHD without major bacterial and fungal infectious complications. Since this sustained alloreactivity might reduce the risk of relapse this regimen could be suited for patients undergoing HCT with advanced or uncontrolled malignant disease.