The Combination of Tacrolimus (T), Sirolimus (S), and Rabbit Anti-Thymocyte Globulin (Thymoglobulin Thymo) to Prevent Acute Graft-Vs-Host Disease (aGVHD) in Patients (pts) Receiving Unrelated Hematopoietic Stem Cell Transplantation (UHSCT).

Acute graft versus host disease aGVHD continues to affect approximately 60% or more of patients undergoing UHSCT, with significant mortality and morbidity. Furthermore viral infections such as Cytomegalo virus (CMV) affect approximately two thirds of these patients.

In a phase II trial, we prospectively evaluated whether adding Thymo (4.5 mg/kg divided doses on days -1,-2, and -3) to Tacrolimus and Sirolimus combination for aGVHD prophylaxis in recipients of UHSCT would decrease the rate of aGVHD. The primary endpoint is aGVHD, which is calculated as cumulative incidence. Since infections are a concern after T cell depletion, the incidence of infections and adverse events were monitored closely.

There were 25 patients (pts) with median age of 51(20-70) years enrolled in the protocol, 10 females and 15 males. There were 10 AML (5CR1, 5CR2), 7 MDS (untreated), 2 ALL (CR1), 1 ALL/AML (uCR1), 1 CML (CP), 1 CMML (untreated), 1 granulocytic Sarcoma (CR1), 1 NKT cell lymphoma (CR3), and 1 DLBCL(CR2). Preparative regimens included Bu/Flu (21 pts), VP16/TBI (2 pts) R-BEAM (1 pt), and Flu/MEL (1 pt). All patients received peripheral blood hematopoietic stem cells (PBHSC) mobilized with granulocyte colony stimulating factor G-CSF with an average CD34+ dose of 8.24×10 ⁶/kg (3.7-14.3). All patients received daily G-CSF starting day +6 till engraftment. After molecular typing, 11 of 25 patients received HLA fully matched graft, 11 of 25 received a 1 antigen (Ag) mismatched graft, and 3 of 25 received a 2 Ag mismatched unrelated PBHSC graft. All patients' engrafted. Median engraftment day is 12 (9,13). Eighteen patients had passed the day 100 time point; seven pts did not reach day 100. Three deaths occurred, due to: relapse (1), multi organ failure (1), and pneumonia (1). Two patients experienced disease relapse. Both went into complete remission once immune suppression was withdrawn, demonstrating clear graft versus Leukemia (GVL) effect, before day 100.

Seven of 25 pts developed aGVHD, 1 developed aGVHD after relapse. Three developed grade 1 aGVHD, 3 pts developed grade 2 aGVHD. One pt developed grade 4 aGVHD after immune suppression withdrawal due to disease relapse. Five patients needed systemic steroids, maximum duration 36 days. All aGVHD cases have responded to therapy. The cumulative incidence rate for aGVHD at 100 days is 0.258 ( 0.101, 0.448); the cumulative incidence rates of competing events: relapse is 0.146 (0.034, 0.334) and death without GVHD or relapse 0.050 (0.003, 0.212).

Patients tolerated Thymo well. Two patients developed thrombotic thrombocytopenic purpura (TTP), one patient after day 100 that required discontinuation of tacrolimus and sirolimus. Four patients developed CMV PCR sub-clinical activation 16% (95% CI 5.7-33.6%), which resolved with treatment. Six patients developed PCR sub-clinical Epstien-barr virus (EBV) activation 20% (95% CI 8.2-38.4), 5/6 needed Rituximab. Three patients developed Herpese simplex virus (HSV) stomatitis, two rhinovirus upper respiratory tract infections, and 3 BK viral cystitis. 14 patients had a documented bacterial infection all resolved. Apart from 2 oral candidiasis, no fungal infections observed. All infections have resolved.

These early results suggest that the combination of Tacrolimus/Sirolimus and Thymo in pts undergoing unrelated HSCT is well tolerated and is associated with a low rate and severity of acute GVHD, and early GVL effect as demonstrated in two patients. Low rates of CMV viral infections were seen. Further accrual and a longer follow-up will be needed to confirm these encouraging results.

Al-Kadhimi:Genzyme pharmacutical: Research Funding. Off Label Use: Thymoglobulin is used to prevent graft versus host disease in unrelated transplant in this protocol. That is an off lable drug use.. Abidi:Merck Pharmaceuticals: Research Funding.