Total Body Irradiation 1350cGy/Fludarabine (TBI/FLU) vs Myeloablative Busulfan/Fludarabine (Bu/Flu) Preparation in Adult Recipients of Dual Umbilical Cord Blood (UCB) Transplantation: Superior Engraftment with Low Treatment-Related Mortality
Authors: Horwitz Mitchell , Chute John , Gasparetto Cristina , Long Gwynn , Rizzieri David , Sullivan Keith , McPherson Jackie , Chao Nelson 
Published: April 2020

A high graft failure rate due to low stem cell dose and high treatment-related mortality have historically been the major pitfalls of myeloablative adult umbilical cord blood transplantation. The goal of this phase II clinical trial was to identify an approach that addresses both of these problems. There is compelling evidence that increasing the cell dose with the use of two partially matched UCB grafts reduces the graft failure rate. While non-myeloablative preparative regimens reduce treatment-related mortality, many patients with high-risk hematologic malignancies may be at increased risk for disease relapse following transplantation. Recently, myeloablative Bu/Flu has gained acceptance as an alternative to standard myeloablative regimens due to published treatment related mortality (TRM) rates as low as 3%. We recently reported an 80% graft failure rate when Bu 130mg/m2 daily × 4 and Flu 160mg/m2 is followed by dual UCB transplantation in adult recipients (Horwitz et al. BBMT 2008). We now report early results of a concurrent cohort of patients, treated on the same prospective clinical trial, who were prepared with myeloablative TBI (1350cGy)/Flu (160mg/m2).

Methods: 16 patients with a median age of 35 (range 21–55) signed consent for the trial. All patients had high risk hematologic malignancies including AML(CR2) 7, ALL(CR1 or CR2) 4, MDS 2, NHL 3. The UCB grafts were at least 4 of 6 matched (antigen level class I, allele level class II) with the recipient and 3 of 6 matched with each other. Each graft contained a minimum cell dose of 1.5 × 107/kg providing a minimum combined total nucleated cell dose of 3 × 107/kg. Tacrolimus and mycophenolate mofetil were used for GvHD prophylaxis and G-CSF was administered until the neutrophil count exceeded 1000/mm3. Voriconazole, acyclovir and ciprofloxacin were used as anti-infective prophylaxis for at least 3 months post transplantation.

Results: With a median follow-up of 15 months, the Kaplan-Meier event-free and overall survival is 61% and 56%, respectively. Three patients experienced graft failure. Hematopoiesis was restored in all three patients with either autologous (2) or allogeneic (1) hematopoietic stem cells. The remainder of patients evaluable for engraftment (competing risk; relapse) achieved &gt;90% donor myeloid chimerism from a single dominant UCB graft. The cumulative incidence of neutrophil engraftment (ANC&gt;500) and platelet engraftment (&gt;50K) is 79% and 75%, respectively. The median time to neutrophil and platelet engraftment was 27 days and 47 days, respectively. Toxic death occurred in 2 patients, resulting in a treatment-related mortality at 6 months of only 9%. In summary, the combination of myeloablative TBI and fludarabine is superior to Bu/Flu in the setting of umbilical cord blood transplantation. This is likely attributable to more effective host immunosuppression provided by the TBI. Acute GvHD occurred in 4 of 9 patients at risk for this complication (Grade II-3, Grade III-1). Chronic GvHD occurred in 2 patients (limited-1, extensive-1). Like the Bu/Flu regimen, we find the TBI/Flu regimen to be well tolerated, resulting in a notably low treatment-related mortality rate compared to more conventional myeloablative drug combinations.

Conclusion: We find the approach consisting of myeloablative TBI/Flu preparation followed by dual umbilical cord blood transplantation in adult patients to be promising and worthy of further investigation.