Tacrolimus and Sirolimus as GVHD Prophylaxis for HLA-MRD Allogeneic HCT Conditioned with 3 Regimens: Toxicity and Efficacy in 70 Patients.

Based on encouraging phase 2 data, we are prospectively testing the combination of tacrolimus and sirolimus (tacro/siro) as GVHD prophylaxis in patients undergoing HLA-MRD HCT. Seventy patients evaluable for this report (>100 days post-HCT) were stratified according to preparative regimen as follows: Fludarabine/melphalan (38), FTBI/VP-16 (23), and Bu/Cy (9). Regimens were given through day -4; tacro/siro was started on day -3 and dosed as published (Cutler et al, BBMT 10 (5), 328–336, 2004). Median age was 50 years (range, 10–67). Diagnoses by regimen were flu/mel: AML (16), NHL (7), MPD (4), HD (4), MM (3), MDS (2), ALL (1), CLL (1); FTBI/VP-16: ALL (12), AML (10), NHL (1); and Bu/Cy: CML (5), MDS (3), AML (1). Stem cell source was PB (n=66) and bone marrow (n=4). Donor gender F:M was 34:36. Median CD34+ cell dose was 5.1 x 10⁶/kg. Median time to neutrophil >500/ml was 15 days (range, 10–26); median day 30 bone marrow MNC chimerism was 100% (65–100%). CTC toxicities >3 were low (2 DAH, 1 ARDS, 1 IP, 1 mucositis); as expected, mucositis was more common with FTBI/VP-16; however, therapeutic sirolimus level was similarly achieved with all conditioning regimens (median level 6.5 ng/ml, range 2.1–61 in the FTBI/VP-16 arm). Opportunistic infections included CMV reactivation (6), Aspergillus pneumonia (2), candidemia (3) and parainfluenza pneumonia (1). Reversible TTP/HUS (IWG definition) was diagnosed in 14 patients (20%) and was more common with Bu/Cy (55%) than with FTBI/VP-16 (22%) or flu/mel (11%); median tacro and siro level in patients with TTP was 9.8 and 15 ng/ml, respectively. Six patients died before day 100 from relapse (2), DAH (2) and multi-organ failure MOF (2), for a day 100 non-relapse mortality of 6%. With a median follow-up of 6 months, 60 patients are alive and 10 patients have died from progressive disease (6), MOF (2) and DAH (2). Disease-free and overall survival at day 100 are 88% and 91%, and at 1 year are 72% and 75%, respectively, with no significant differences by regimen. Acute GVHD grade 2–4 and 3–4 was observed in 25 (36%) and 13 patients (19%), respectively; by conditioning regimen, grade 2–4 acute GVHD incidence was: flu/mel, 11/38 (29%); FTBI/VP-16, 9/23 (39%); and Bu/Cy, 5/9 (56%). A temporal relationship between GVHD and TTP could not be established, with some patients developing GVHD before and others after TTP. Chronic GVHD has been diagnosed in 17/45 evaluable patients. This study shows a low TRM when tacro/siro is given with 3 different conditioning regimens; adequate sirolimus levels can be achieved even in patients with significant mucositis; a high incidence of TTP in patients conditioned with Bu/Cy suggests synergistic endothelial toxicity with this combination. Acceptable rates of acute GVHD in this study support plans for a national phase 3 study comparing tacro/siro with tacro/methotrexate.