Comparable Toxicity between Fludarabine/Full dose i.v. Busulfan and Fludarabine/Melphalan in Allogeneic PBSC Transplantation.

Previous studies have demonstrated the efficacy of Fludarabine and full dose i.v. Busulfan as conditioning regimen in allogeneic hemopoietic stem cell transplant (HSCT). In this study we analyzed 22 patients who received an allogeneic HSCT from matched related (n=17) or unrelated (n=5) donors, and were conditioned with FLU/BU (fludarabine 30 mg/m²/d x 4 days followed by single dose i.v. busulfan 3.2 mg/kg/d x 4 days) (n=12) or FLU/MEL (fludarabine 30 mg/m²/d x 5 days and melphalan 70 mg/m²/d x 2 days) (n=10). Median age was 26 yrs (range:19–51) in the FLU/BU group and 47 yrs (range:22–57) in the FLU/MEL group (p=0.02). Also, patients at high risk were 8/12 in the FLU/BU group (7 AML in relapse, 1 CML-AP) and 3/10 in the FLU/MEL group (2 resistant NHL and 1 HD) (p=0.08). Patients received GVHD prophylaxis with FK-506 and MTX and in 9/12 FLU/BU cases (including 5 MUD) also with Thymoglobulin. HSC source was G-CSF mobilized peripheral blood in all FLU/MEL and 6/12 FLU/BU patients, while the remaining 6 received bone marrow cells. Median numbers of infused CD34+ cells were: 1.58 x 10⁶/kg in FLU/BU patients receiving marrow grafts, while 5.0 and 5.9 x10⁶/kg, respectively, in FLU/BU and FLU/MEL patients who received PBSC. Median time to ANC >500 was comparable in PBSC FLU/BU (d14, range: 11–20), and PBSC FLU/MEL (d12, range: 10–15) patients, while it was significantly longer in bone marrow FLU/BU (d 22, range:17–37) patients (p= 0.01 and p=0.001, respectively). Similarly, time to Plt >20K was d 12 (range: 10–16) in the PBSC FLU/MEL group and d 20 (range: 17–37) in the bone marrow FLU/BUS group. Interestingly, 4 of 6 PBSC FLU/BU patients did not have severe thrombocytopenia (<20K) after transplant. Mucositis > grade 2 was never observed in these two groups. Median length of stay (LOS) in the hospital after transplant was 17 days (range:13–37) in PBSC FLU/MEL, 23 days (range: 18–42) in PBSC FLU/BU and 30 d (range: 22–38) in bone marrow FLU/BU (p=n.s.). Median chimerism levels on d30 after transplant were: 100% in FLU/MEL and 95% in FLU/BU. One patient in the bone marrow FLU/BU experienced a graft rejection and was retransplanted succesfully. Median follow-up is 137 days (range: 42–548) in the FLU/BU group and 552 days (range: 157–633) in the FLU/MEL group. Acute GVHD was limited (grade 1 in 5/12 FLU/BU vs 1/10 FLU/MEL, and > grade 1 only in 1 FLU/MEL patient), and chronic GVHD is present in 1/4 FLU/BU and 4/9 FLU/MEL evaluable patients. Six of 12 patients in the FLU/BU died of: relapse (n=4) and/or infection (n=2, but only 1 within d100 ) and 3 of 10 patients in the FLU/MEL died, all of relapse. In conclusion, despite the small series of patients, the FLU/BU and FLU/MEL regimens seem to have similar limited toxicity in allogeneic PBSC transplantation. Due to its safety, an allotransplant conditioned with FLU/single dose i.v. BU could be applied also to elderly patients and may represent a platform for donor lymphocyte infusions in high risk patients.