Pulse Cyclophosphamide in the Treatment of Liver GvHD Unresponsive to Steroids.

Introduction: Steroids provide an active but inadequate therapy for acute GvHD. Corticosteroid-resistant acute GvHD is extremely difficult to manage and is associated with very high morbidity and mortality. Cyclophosphamide (Cy) has been used for a long time as an immunosuppressive drug for the treatment of many autoimmune disorders, as a cytotoxic drug, and Cy is also a part of both classical conditioning regimens, Cy+TBI and Cy+busulfan. Pulse Cy at a dose of 1 g/m2 is now an established mainstay in the treatment of lupus nephritis. Therefore, we hypothesized that this pulse treatment can be used also for steroid-refractory GvHD. In a previous work, we showed that intestinal GvHD responded poorly to pulse Cy, whilst liver, skin, and oral GvHD responded very well. Since steroid-refractory acute skin GvHD is not frequent, in this report, we analyzed our new data concerning liver GvHD.

Patients (pts) and methods: This is a retrospective study of 17 pts: 11 pts had acute GvHD, 3 pts had chronic GvHD (albeit progressing from acute GvHD), and 4 pts developed liver GvHD upon DLI. Seven pts had hepatitic variant of liver GvHD (serum aminotransferase ALT or AST elevation >10 times the upper normal limit). Seven pts had steroids plus another previous therapy before receiving Cy pulse.

Results and Conclusions: There were 21 Cy administrations at the dose of about 1 g/m2 (460 mg/m2 – 1500 mg/m2, median dose: 1000 mg/m2). The dose was empirically decreased or increased because of fear of myelosuppression, or previous incomplete response, respectively. There were 47% CR (8/17), 18% (3/17) PR, and 35% (6/17) NR. However, in 4 pts with NR their clinical status stabilized and they responded to another treatment. Four pts died: 2 from intractable liver and intestinal GvHD, 1 from intestinal GvHD with liver GvHD in PR, and 1 from relapsing leukemia. All GvHD related deaths occurred in pts with acute GvHD, whereas all but one pts (relapsing AML) with post-DLI or chronic GvHD survived. Concomitant severe gut GvHD seems to be the risk factor for not reaching CR in liver GvHD, and death. On the other hand, however, 6/7 pts (86%) with hepatitic GvHD reached CR. Pulse Cy exerts a good toxicity profile, except for a manageable, short-term myelosuppression in some patients, and does not appear to increase the risk of opportunistic infections, mixed chimerism, relapses, or posttransplant lymphoproliferative disease. The cost of the drug is negligible.