Prevention of acute (A) and chronic (C) GVHD remains a challenge in AlloSCT, especially with the increasing use of HLA-disparate donors. Standard approaches have included cyclosporine (CSA) with methotrexate (MTX) or prednisone (PRED) in R donor and cord blood (CB) transplant, and T-cell depletion or CD-34 positive selection in UR donor transplant. Mucositis and hepatic dysfunction due to MTX and chronic toxicities of PRED limit their use. FK506 is similar to CSA but more effective in preventing grade II-IV AGVHD (Hiraoka et al, BMT 2001; 28:181-5; Ratanatharathom et al, Blood 1998; 92:2303-14). MMF is an antiproliferative agent that inhibits IMDPH and de-novo purine synthesis especially in proliferating lymphocytes. FK506/MMF is effective salvage therapy for steroid-resistant CGVHD (Mookerjee et al, BMT 1999; 24:517-20), but this combination has not been evaluated extensively as a prophylaxis regimen. We treated 11 patients (pts) (age 2-22 years, median 13 years; 6 male, 5 female) undergoing AlloSCT for ALL CR2 (3), relapsed/refractory AML (2), CML-CP (1), lymphoblastic lymphoma CR2 (1), HD CR2 (2), refractory HD (1), or AA (1) with a regimen of FK506 0.03 mg/kg/day by CIVI or 0.12 mg/kg PO BID starting day -1 (target level 10-20 ng/ml) and MMF 15 mg/kg BID starting day +1. In submyeloablative transplant recipients (4/11) with less than grade II AGVHD, MMF was stopped on day +28 and FK506 tapered between day +60 and +120. In fully myeloablative transplant recipients, both drugs were tapered starting at day +100. HLA typing was by serology for A and B loci and high resolution for DRB1. Stem cell sources were UR donor CB (1 5/6 and 6 4/6 matched [M], with 2 class I/II mismatch [MM], 3 class I double MM, 1 class II double MM, and 1 class I MM), R donor PBSC (3 6/6 M), and R donor BM (1 6/6 M). FK506/MMF was well tolerated with 1 possible case of grade 3 neurotoxicity. Nine of 11 pts were evaluable for ANC recovery and survival; 1 died prior to engraftment, 1 had primary graft failure. Median duration of MMF and FK506 administration was 43.5 days (17-127) and 50 days (15-166), respectively. Median time to ANC recovery (>500/mm3 x 2 days) following UR donor CB transplant was 26.5 days (4-80), and R donor SCT 14 days (12-18). Only 3 evaluable patients (33%) developed AGVHD: reversible grade II (skin) in an UR donor CB recipient, grade II (intestinal) in a R donor PBSC recipient, and grade IV (skin, intestine, and liver) in an UR donor CB recipient (following 4 consecutive days of sub-therapeutic FK506 levels). The incidence of severe (grade III/IV) AGVHD was only 11%, and no pt developed CGVHD, although follow-up is brief. There were 6 documented opportunistic infections (1 herpes zoster, 2 adenovirus, 2 CMV, and 1 pulmonary aspergillus), and 4 pts died (1 pulmonary hemorrhage, 1 Pseudomonas sepsis, 1 disseminated adenovirus, and 1 progressive disease). These preliminary results suggest that FK506 and MMF is a tolerable regimen which does not delay myeloid engraftment and may be an effective MTX- and steroid-sparing GVHD prophylaxis regimen following R and UR donor AlloSCT, respectively (including CB transplant). Larger studies with longer follow-up with this regimen are needed and comparatives studies with standard GVHD regimens will be required in the future to determine the safest and most effective approach to prevent acute and chronic GVHD following allo SCT.
Full conference title:
43rd American Society of Hematology (ASH) Annual Meeting
- ASH 43rd (2001)