Sirolimus, Tacrolimus and Low-Dose Methotrexate Based Graft-Versus-Host Disease (GVHD) Prophylaxis After Non-Ablative or Reduced Intensity Conditioning in Related and Unrelated Donor Allogeneic Stem Cell Transplantation: Decreased Severe Early aGVHD but Persistence of Late Acute Gvhd

The morbidity and mortality associated with acute and chronic graft-versus-host disease (GVHD) remain significant after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Encouraging results have been reported with the combination of sirolimus, tacrolimus, and low-dose methotrexate after non-myeloablative allogeneic peripheral blood stem cell transplantation (PBSCT) (Alyea EP et al, Biol Blood Marrow Transplant 2008). We conducted a retrospective analysis of 74 patients with hematologic malignancies who underwent a non-myeloablative (NMA) or reduced intensity (RIC) allo-HSCT using sirolimus, tacrolimus, and low-dose methotrexate for GVHD prophylaxis.

Between April 2008 and June 2011, 74 patients (M/F: 45/29), median age 51 years (range: 23–69) were transplanted for non-Hodgkin's lymphoma (63%), chronic lymphocytic leukemia/small lymphocytic lymphoma (20%), Hodgkin lymphoma (12%) and acute lymphoblastic leukemia or myelodysplasia (3%). At transplantation, 36 patients (49%) were in complete remission and 38 patients (51%) had chemotherapy sensitive active disease. Conditioning regimen was NMA in 59 patients and RIC in 15 patients. Donors were HLA-matched related (MRD, n = 30, 41%), matched unrelated (MUD, n = 37, 50%) or 9/10 HLA-mismatched unrelated (MMUD, n = 7). All patients received peripheral blood mobilized grafts. GVHD prophylaxis consisted of sirolimus and tacrolimus that were started on day -3 and doses were adjusted to maintain target serum trough levels of 3–12 ng/mL and 5–10 ng/mL, respectively, followed by methotrexate 5 mg/m² on days +1, 3, 6. Tapering of sirolimus and tacrolimus began at day 60 in the absence of GVHD or relapse, with the goal of complete discontinuation of immunosuppressants by 6 months or earlier if patients were not in CR at transplant. Recipients of MUD (31 of 37) or MMUD (7 of 7) grafts were given 2 doses of anti-thymocyte globulin (ATG) on days −3, and −2. Forty-eight patients with CD20+ malignancies (65%) received rituximab at day -8 and +21, 28, 35, 42. Acute GVHD (aGVHD) was scored by IBMT Severity Index and chronic GVHD (cGVHD) based on NIH consensus criteria.

The cumulative incidence of Grade B-D and C-D classic aGVHD at day +100 were 14.9% and 2.7%, respectively. The cumulative incidence of aGVHD at 1-year was 31.1 % for grade B-D and 5.4 % for grade C-D, due to late-onset Grade B-D and Grade C-D aGVHD rates of 16.2% and 2.7%, respectively. The incidence of cGVHD at 1 and 2 years was 15% and 28%, respectively. The use of peri-transplant rituximab did not affect the incidence of Grade B-D aGVHD (p=0.55) or cGVHD (p=0.94). There was no difference in the incidence of Grade B-D aGVHD at day 100 between ATG (13.9%) and no ATG (15.8%) cohorts. There was a trend towards a modestly higher 2-year incidence of cGVHD in patients who did not receive ATG, despite the fact that these were predominantly recipients of MRD (37% vs. 21% in ATG cohort, p=0.12). Two patients (2.7%) developed thrombotic microangiopathy and 4 patients (5.4%) had renal toxicity, requiring modification of the immunosuppressant treatment. No sinusoidal obstructive sydrome was reported. To date, 15 patients have died; causes of death include disease recurrence (n=9) and GVHD (n=6). The cumulative incidence of non-relapse mortality and relapse at 1 year were 4% and 27%, respectively. The 1-year relapse rate in the ATG and no ATG cohorts was 11% and 28%, respectively (p=0.10). With a median follow up 2.6 (range: 0.8–3.9) years, progression-free and overall survival at 2 years were 64 % and 77 %, respectively.

As previously reported this GVHD prophylaxis regimen is safe and effective, providing lower rates of acute GVHD compared to historical data. The incidence of chronic GVHD by NIH criteria was low due to an increase in late-onset acute GVHD. Rituximab therapy did not affect the incidence of acute and chronic GVHD. The addition of ATG in MUD and MMUD recipients resulted in a trend toward lower rates of chronic GVHD with no increase in the rate of relapse. Future strategies will need to focus on decreasing the incidence of late onset acute and chronic GVHD without increasing the risk of relapse.

No relevant conflicts of interest to declare.