A Prospective Phase II Trial: The Combination of Tacrolimus, Sirolimus, and Rabbit Anti-Thymocyte Globulin (Thymoglobulin® Thymo) to Prevent Acute Graft Vs. Host Disease (aGVHD) in Patients Receiving Unrelated Hematopoietic Stem Cell Transplantation (UHSCT)

Acute graft versus host disease continues to affect approximately 60% of patients undergoing UHSCT, with significant mortality and morbidity.

We prospectively evaluated the efficacy of combining Thymo (4.5 mg/kg divided doses on days -1,-2, and -3), tacrolimus and sirolimus in preventing aGVHD. The cumulative incidence (CI) rate of grade II-IV aGVHD was calculated using death without grade II-IV aGVHD and relapse as competing risks (Cr). The Cr: for non relapse mortality (NRM) CI was death due to relapse, for relapse CI was death without relapse, for chronic GVHD CI was relapse & non relapse mortality without cGVHD. Kaplan-Meier method was used to calculate overall (OS) and progression free survival (PFS). The incidence of infections and other complications were reported with the Wilson's 95% Confidence Interval (in table below).

Between August 2008 and November of 2010, we enrolled 47 patients (pts) with median age of 50(20–70) years. The Median follow-up time is 23.6 months (18.8–27.9). There were 21 AML, 10 MDS, 4 ALL, 2 CML, 2 CMML, 1 CLL, 3 Myelofibrosis, 2 multiple myeloma, 2 NHL. Preparative regimens included Bu/Flu 30, Bu/Flu-TBI 10, VP16/TBI 3, R-BEAM 1, and Flu/MEL-TBI 3. All pts received peripheral blood stem cells mobilized with G-CSF. Median CD34+ dose was 7.31×10 ⁶/kg (1.9–18.6). Median donor age was 32.6 (19.0–61.0) years. All patients received daily G-CSF starting day +6 till engraftment. Twenty two pts received 8/8 and 25 received 7/8 HLA matched grafts respectively. All patients' engrafted, with median day of 11 (9–15). Twenty deaths occurred throughout the whole follow up period, due to: relapse 6, aGVHD 4, cGVHD 2, sinusoidal obstruction syndrome (SOS) 2, bleeding 1, multi organ failure 2, sepsis 2 and pneumonia 1. Twelve patients experienced disease relapse. Fourteen patients had non-relapse mortality.

Twelve pts developed Grade II-IV aGVHD, 5 grade II, 4 grade III, and 3 grade IV. The CI rate for grade II-IV aGVHD at 200 days post transplant is 0.23.4% (12.4, 36.3); CI of NRM at day 1057 is 31.9% (18.4, 46.2). CI of relapse at day 1057 is 30.4% (15.2,47.1). CI of cGVHD at day 890 is 40.2(21.5, 58.2), with total of 16 cases: 8 mild, 7 moderate and one sever based on NIH consensus criteria. Median PFS is 17.7 months. PFS at 6 months is 63% and 54% at 1 year. Median OS has not been reached. OS at 6 months is 73%, and 65% at one year. The incidence of infections and other transplant related morbidities are shown in the table below. There were 2 cases of thrombotic thrombocytopenic purpura (TTP) before day 100. 16 CMV by PCR, 10 EBV by PCR, 9 HSV, 10 BK cystitis, 31 bacterial infections, 4 oral candidiasis, and 3 SOS.

These early results suggest that the combination of Thymo, tacrolimus and sirolimus in pts undergoing UHSCT is well tolerated and is associated with a low rate and severity of acute GVHD.

Al-Kadhimi:Genzyme Pharmaceuticals: Research Funding. Off Label Use: The use of thymoglobulin, Sirolimus and Tacrolimus in blood and marrow transplant. Lum:Transtarget Inc: Equity Ownership, Founder of Transtarget.