Low Dose Fludarabine Is an Effective Conditioning Treatment to Suppress Relapse Rate in PT-CY-Based Haploidentical Peripheral Blood Stem Cell Transplantation

Background:

Haploidentical related donors are alternative donors for patients in the absence of a HLA-matched donor and in an urgent need of transplantation. However, haploidentical PBSCT (haploPBSCT) pose significant challenges due to HLA mismatch, which often leads to increased risk of graft versus-host disease (GVHD) and non-relapse mortality (NRM). A recent study led by the Johns Hopkins group pioneered the use of post-transplant cyclophosphamide (PTCY) in the haploPBSCT setting. The study used mostly reduced-intensity conditioning (RIC) and reported significant reductions in NRM and GVHD. However, high rate of relapse is problem that still needs to be addressed. To resolve high rate of relapse, we used a 3-day schedule of fludarabine (30mg/m² x 3days; 3-day fludarabine) from 5-day schedule of fludarabine (30mg/m² x 5days; 5-day fludarabine) as a preparation regimen in PTCy-haploPBSCT settings, and report the outcome.

PatientsandMethods: 35 patients were enrolled. The median age was 61(range, 24 to 71); AML (31%), ALL (14%), MDS (46%) and NHL (9%). The first 9 patients were enrolled in a 5-day fludarabine regimen; after that, 26 patients received a 3-day fludarabine regimen. The conditioning regimen consisted of a combination of busulfan (6.4 mg/kg), total body irradiation (TBI, 3Gy), and 3-day or 5-day fludarabine. High-dose cyclophosphamide (50 mg/kg/day on days 3 and 5), cyclosporine, and MMF were used for GVHD prophylaxis. The median number of CD34⁺ cells of PBSCs was 10.74×10⁶ cells/kg (range, 4.97-24.38×10⁶ /kg).

Results:

Interestingly, the cumulative incidence of relapse at 2 years was 0% in the 3-day fludarabine group, compared to 33% in the 5-day fludarabine group (HR 0.001; 95% CI: 0.00-2168; p=0.006). At median follow-up of 12 months (range, 0-38), 3-day fludarabine significantly reduced the risk of disease progression or death by 49% compared with 5-day fludarabine. The median PFS was not evaluable (NE) in the 3-day fludarabine group and 4 months in the 5-day fludarabine group (HR 0.271; 95% CI: 0.083-0.83; p=0.019). Three-day fludarabine reduced the risk of death by 44% compared with the 5-day fludarabine group. OS was longer in the 3-day fludarabine group with NE versus 18 months (HR 0.364; 95% CI: 0.108-1.228; p=0.088). In the 3-day fludarabine group (n=26), the cumulative incidences of grades II-IV acute GVHD, grades III-IV acute GVHD, and chronic GVHD were 17%, 11%, and 27%, respectively. In the 5-day fludarabine group (n=9), the cumulative incidence of grades II-IV acute GVHD, grades III-IV acute GVHD, and chronic GVHD were 41%, 17% and 17%, respectively. The two-year GVHD-free, relapse-free survival (GRFS) significantly increased in the 3-day fludarabine group (55%) compared with 5-day fludarabine group (22%; p=0.05).

Conclusions: Our results indicate that 3-day fludarabine, busulfan, and low-dose TBI is an effective conditioning treatment in PTCy-haplo PBSCT setting. 3-day fludarabine is a valid and safe strategy for preventing relapse rate and may provide better clinical outcomes in long-term disease control.

Keywords: Fludarabine, Post-transplant cyclophosphamide; haploidentical peripheral blood stem cell transplantation; GVHD.

Kim:St. Vincent's Hospital, The Catholic University of Korea, Suwon, South Korea: Current Employment; Ministry of Science and Technology of Korea: Research Funding.