Double Umbilical Cord Blood Transplantation after Novel Myeloablative Conditioning Using a Regimen of Fludarabine, Busulfan, and Total Lymphoid Irradiation

Abstract

We conducted a pilot study evaluating double umbilical cord blood transplantation (dCBT) after myeloablative (MA) conditioning with Fludarabine/Busulfan 3.2mg/kg IV × 4, followed by Total Lymphoid Irradiation at 400cGy (FluBu4/TLI) for any indicated hematological disorder without a suitable donor. Twenty patients with predominantly high-risk disease underwent dCBT according to protocol. The regimen was well tolerated, with mucositis as the primary observed toxicity (n=19). The cumulative incidence of neutrophil engraftment was 89% (95% C.I., 64-97%), with a median time to recovery of 16 days (range: 12-31 days). All evaluable patients with neutrophil engraftment achieved complete donor chimerism by day 40. The cumulative incidence of grade III/IV acute GVHD at day 100 was 10% (95% C.I., 2-27%), and the cumulative incidence of chronic GVHD was 35% (95% C.I. 16-55%) by the end of the study. At one year, the cumulative incidence of treatment related mortality (TRM) was 35% (95% C.I. 16-55%). The leading cause of non-relapse mortality was acute GVHD (n=4), followed by graft failure (n=2), and chronic GVHD (n=1). Treatment-related mortality was significantly associated with a pre-transplant HCT-CI score ≥3 (p=0.005). At one year, disease relapse occurred in six patients, and overall survival was 40% (95% C.I. 19-60%). We conclude that MA FluBu4/TLI is an adequate preparative regiment prior to dCBT, providing high engraftment rates, and relatively early neutrophil recovery. The best survival outcomes were seen in patients without significant comorbidities pre-transplant, and are comparable to previously published dCBT studies.

Adult Umbilical Cord Blood Transplantation Using Myeloablative Thiotepa, Total Body Irradiation, and Fludarabine Conditioning

“…The myeloablative regimen of thiotepa, busulfan, fludarabine, and anti-thymocyte globulin is also associated with a low early TRM of 20% at 180 days, but this regimen has been studied in a considerably younger population of patients receiving single UCB transplantation 7, 24, 25 . At one and three years after TBI, fludarabine, and thiotepa, TRM increased to 24% and 30%, respectively, similar to later TRM rates observed with other myeloablative regimens 5, 9, 10, 24, 25 . The encouraging low early TRM with thiotepa, TBI, and fludarabine may reflect decreased regimen-related toxicity, while the rise in later TRM may be influenced by other factors such as graft versus host disease and immune reconstitution.…”

“…This improved rate of neutrophil engraftment may be related to the described immunosuppressive property of thiotepa 14 . Furthermore, neutrophil engraftment with the thiotepa, TBI, and fludarabine regimen was comparable to engraftment rates ranging from 86% to 94% in recent reports of other myeloablative conditioning regimens for adult UCB transplantation 5, 9, 24, 25 .…”

“…Several alternative myeloablative conditioning regimens have been developed in an attempt to reduce regimen-related toxicity 7–9 . We previously conducted a trial of double UCB transplantation using a modified myeloablative regimen of TBI and fludarabine 10 .…”

Hematopoietic Stem Cell Source and Storage

“…Conditioning regimens were either the widely accepted Minnesota protocol, which consisted of TBI/cyclophosphamide/ fludarabine or thiotepa/busulphan/fludarabine (TBF). In this study, 2 years LFS was similar between double-unit cord and single-unit cord if the new TBF protocol was chosen [75,77]. In a prospective multicenter trial, which included 56 acute leukemia and myelodysplasia patients transplanted with double-unit cord, 3 years disease-free survival was 50% and TRM was 39% [76].…”

A Novel Reduced-Toxicity Myeloablative Conditioning Regimen Using Full-Dose Busulfan, Fludarabine, and Melphalan for Single Cord Blood Transplantation Provides Durable Engraftment and Remission in Nonremission Myeloid Malignancies

“…In the setting of CBT, the FluBu regimen has not been widely accepted because of a high rate of engraftment failure reported in several studies [4,11]. Recently, some investigators reported successful engraftment of CB units by adding low doses of total-body irradiation (TBI), thiotepa, or antithymocyte globulin (ATG) to the FluBu4 regimen [12][13][14][15], suggesting that additional immunosuppressive agents would be crucial to overcome rejection. Our retrospective analysis of various FluBu regimens in CBT confirmed that adding melphalan (Mel), a DNA alkylating agent with both immunosuppressive and myeloablative properties [16,17], to FluBu regimens has potential to achieve successful engraftment without increasing NRM [15].…”