Two major strategies to reduce CMV disease in AlloSCT recipients are prophylaxis and/or pre-emptive therapy with ganciclovir (Wingard, Blood and Marrow Trans Rev 2003). CMV prophylaxis with Gan post AlloSCT reduces the incidence of CMV disease to 3%, but is associated with a 40% incidence of grade III/IV hematologic toxicity (Goodrich, NEJM 1991). Pre-emptive treatment in pediatric AlloSCT recipients following PCR detection of CMV DNAemia is less effective, resulting in a 40% incidence of CMV disease (Matthes-Martin, Bone Marrow Transplant 2003). Fos is an effective agent against CMV (Oberg, Pharmaco Ther 1989), but has dose limiting renal toxicity (Deray, Am J Nephrol 1989). Combination Gan/Fos is more effective than monotherapy in CMV retinitis in HIV pts (Peters, J Inf Dis 1994). Since both Gan and Fos are effective against CMV but have different toxicity profiles and dose-limiting toxicities, we evaluated the safety and efficacy of alternate day Gan/Fos in pediatric AlloSCT recipients who were CMV seropositive (SP) and/or received CMV SP donor cells. AlloSCT pts (n=9) that were serologically CMV (-) donor/(-) recipient received leukodepleted blood products (LDBP). AlloSCT pts (n=18) that were either SP and/or donors SP for CMV received prophylaxis with IV Fos at 90 mg/kg Q48H alternating with IV Gan at 5 mg/kg Q48H, initiated at the time of myeloid recovery (ANC 750/mm3) until D +100. Patient demographics: M:F 14:13; mean SD age 105.99 (0.8-18 yr); 1 APL CR2, 1 Wilms SD, 1 Hurlers SD, 2 CML CP, 3 AML CR2 , 3 SAA, 2 ALL CR2, 2 Beta-Thal, 1 ALL CR3, 1 HD PR2, 2 HD CR2, 1 ALCL PR, 1 NBL CR, 1 NBL PR, 1 NBL PD, 1 Fanconis anemia, 2 MDS SD, 1 HLH. Donors: 7 HLA matched related peripheral blood donors (RPBSC) 6/6, 1 RPBSC 5/6, 3 related bone marrow (RBM) 6/6, 1 RBM 5/6, 1 related cord blood (RCB) 5/6, 1 unrelated adult PBSC (UPBSC) 6/6, 4 unrelated cord blood (UCB) 5/6, 7 UCB 4/6. GVHD prophylaxis: tacrolimus/mycophenolate mofetil. Mean SD total nucleated count (TNC) and CD34 for BM/PBSC 6.39 5.9 x108/kg and 5.1 3.5 x 106/kg, respectively, and CB TNC and CD34 were 4.6 3.3 x107/kg and 2.2 2.1 x 105/kg, respectively. Despite an incidence of 36% grade II-IV AGVHD (n=36), none of the patients developed systemic CMV disease. There was 19% grade III/IV hematologic toxicity secondary to Gan. Pts developed transient nephrotoxicity and electrolyte imbalances, however no pt developed permanent renal dysfunction and all pts were on at least 2 other nephrotoxic drugs: liposomal amphotericin B (n=27), tacrolimus/cyclosporine (n=25/2), aminoglycosides (n=14), vancomycin (n=21), and cidofovir (n=5). Dose reductions of Fos/Gan occurred in 67% (18/27) of pts. The probability of 1 yr. OS in Gan/Fos recipients was 74% (20/27). In conclusion, CMV prophylaxis in AlloSCT recipients with alternate day Gan/Fos in at-risk pts SP recipients and/or donors and with LDBP in SP (-)recipients (-)donors appears to be tolerable and 100% effective in preventing CMV disease. This regimen may be associated with a Fos-induced transient electrolyte imbalance and/or nephrotoxicity, especially in combination with other nephrotoxic agents.
Full conference title:
American Society of Hematology 45th Annual Meeting
- ASH 45th (2003)