HLA Haplo-Identical Peripheral Blood Stem Cell Transplantation Using High-Dose Cyclophosphamide Post-Transplantation For Poor Prognosis Or Refractory Acute Leukemia and Myelodysplastic Syndrome: A Prospective Pilot Study At a Single Center

Recently nonmyeloablative, haplo-identical T-cell replete bone marrow transplantation using high-dose cyclophosphamide (CY) post-BMT to control GVHD and prevent graft rejection by inducing bi-directional tolerance was reported. This strategy resulted in promising outcomes with low transplantation-related mortality (TRM) due to a low incidence of GVHD and infectious disease. However, the high relapse rate remained a major problem in high-risk hematological disease. We therefore planned a prospective pilot study of myeloablative or reduced intensity HLA haplo-identical allogeneic hematopoietic cell transplantation (HCT) using reduced doses of CY post-transplantation, followed by administration of peripheral blood stem cells (PBSC) instead of bone marrow, for those with a poor-prognosis or refractory leukemia and MDS.

As of 30 June 2013, 17 patients had been enrolled in this prospective pilot study. Patients with a poor prognosis or refractory leukemia and MDS requiring prompt HCT were eligible for this study if they lacked a donor who was serologically HLA-identical or had a single antigen mismatch.

The conditioning regimen consisted of fludarabine 15 mg/m² and cytarabine 2.0 g/ m² twice a day on days -11 and -10, thymoglobulin 2.0 mg/kg on days -8 and -7, and fludarabine 30 mg/ m²/day with intravenous busulfan 3.2 mg/kg/day on days -6 to -3 (n=11) or melphalan 100 mg (n=6) on day -2. Nine patients received a single dose of 25 mg/kg CY on day 3 and eight patients, double doses of 25 mg/kg CY on days 3 and 4 post-peripheral blood stem cell transplantation (PBSCT). Tacrolimus and oral mycophenolate mofetil was started after the completion of high-dose CY post-HCT.

The median age of patients was 42 years (range 18–65). Disease diagnoses included AML (n=14), ALL (n=2) and MDS (n=1). In 12 (71%) of 17 patients, disease status was non-remission, with active disease at the time of PBSCT. Eight (47%) of 17 patients had a history of prior HCT. Donors were partially HLA-mismatched (haplo-identical) first degree relatives of the patients and differed from the patients at a median of 3/8 HLA loci in both the HVG and GVH directions. All patients received G-CSF-mobilized, unmanipulated PBSC containing a median of 3.0 x 10⁶ CD34+cells/kg and 1.4 x 10⁸CD3+T-cells/kg.

Non-infectious fever due to PBSC infusion occurred in 14 (82%) patients and persisted until day 2 in most patients. Except for one patient who died soon after PBSCT due to disease progression, full donor T-cell chimerism was achieved at day 30 following PBSCT in all patients. Nine of 17 developed grade II-III acute GVHD. None developed grade IV acute GVHD. Three of nine patients receiving a single dose of CY, but only one of eight patients receiving double doses of CY developed grade III acute GVHD. In 12 of 16 evaluable patients, CMV reactivation was observed by day 100. Three patients developed CMV disease. BK virus cystitis occurred in four of eight patients receiving double doses of CY, however, none receiving a single dose of CY post-PBSCT developed BK virus cystitis. The cumulative incidence of TRM at one year was 13%. At one year, the overall survival of all patients, and the percentages of patients in remission and those with active disease were 43%, 75% and 31%, respectively.

The results of our study demonstrated that our HLA haplo-identical transplantation using high-dose CY post-PBSCT resulted in a low incidence of TRM and was feasible even in patients with high-risk acute leukemia and MDS as an alternative stem cell source. Of note, the dose of CY post-PBSCT affected the incidence of both BKV cystitis and severe GVHD. The optimal dose of CY following HLA haplo-identical PBSCT and preparative regimen should be further explored to establish a standard regimen.