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

Abstract

Treatment related mortality (TRM) remains elevated in adult patients undergoing umbilical cord blood (UCB) transplantation, including an early rise in TRM suggestive of excessive toxicity associated with the standard myeloablative total body irradiation (TBI), fludarabine, and cyclophosphamide regimen. In an attempt to reduce regimen-related toxicity, we previously studied a modified myeloablative regimen with total body irradiation (1350 cGy) and fludarabine (160 mg/m2); TRM was decreased but neutrophil engraftment was suboptimal. Therefore, in order to improve engraftment while still minimizing regimen-related toxicity, we piloted a myeloablative regimen with the addition of thiotepa (10 mg/kg) to TBI and fludarabine conditioning. Thirty-one adult patients (median age 46 years; range, 19–65) with hematologic malignancies (acute leukemia/MDS 77%, lymphoid malignancy 23%) underwent single (n=1) or double (n=30) UCB transplantation from 2010 to 2015 at our institution. The cumulative incidence (CI) of neutrophil engraftment was 90% (95% CI, 70–97%) by 60 days, with a median time to engraftment of 21 days (95% CI, 19–26 days). The CI of platelet engraftment was 77% (95% CI, 57–89%) by 100 days, with a median time to engraftment of 47 days (95% CI, 37–73 days). Cumulative incidences of grades II–IV and grades III–IV acute GVHD at day 100 were 45% (95% CI, 27–62%) and 10% (95% CI, 2–23%), respectively. The overall incidence of chronic GVHD at 2 years was 40% (95% CI, 22–57%), with 17% (95% CI, 6–33%) of patients experiencing moderate to severe chronic GVHD by 2 years. Treatment-related mortality at 180 days was 13% (95% CI, 4–27%), while at 1 year was 24% (95% CI, 10–41%) and at 3 years was 30% (95% CI, 13–49%). Relapse at 1 year was 13% (95% CI, 4–27%) and at 3 years was 19% (95% CI, 6–38%). With a median follow-up of 35.5 months (95% CI, 12.7–52.2 months), disease-free and overall survival at 3 years was 51% (95% CI, 29–69%) and 57% (95% CI, 36–73%), respectively. This regimen represents a reasonable alternative to myeloablative conditioning with TBI, fludarabine, and cyclophosphamide and warrants further study.

Cord-Blood Engraftment Using an Enhanced Dual-Conditioning Regimen for Malignant Hematologic Diseases

“…A series of studies have shown that TT is added to modified BuCy2 37 , MEL is added to FB 38 , Flu or Ara-C is added to the CyTBI regimen 1,5,11,39,40 , and a conditioning regimen composed of TT, TBI, and fludarabine 9 shows improved engraftment and survival in UCBT. These alternative enhanced conditioning regimens have become preferable protocols for UCBT.…”

“…Graft failure (GF) and delayed engraftment restrict the application of umbilical cord blood transplantation (UCBT). Engraftment is successful in approximately 80%-90% of patients with UCBT [1][2][3][4][5][6][7][8][9][10] , and the remaining 10%-20% of patients do not become engrafted. It has always been believed that the limiting factor in UCBT is the low number of hematopoietic stem cells (HSCs) in cord blood units (CBUs); therefore, various strategies have been explored to increase the number of HSCs [11][12][13][14][15][16][17][18][19] .…”

Umbilical cord blood stem cells: clinical application of allogeneic material, problems and perspectives of banking

“…Серед альтернативних кріопротекторних агентів використовують етиленгліколь, 1,2-пропіленгліколь, поліетиленоксид (ПЕО-1500, ПЕО-400), ПВП, гідроксицелюлозу, дисахариди (сахарозу, мальтозу, трегалозу), а також макромолекули декстрану, гідроксиетилового крохмалю тощо. Їх застосовують як основні кріопротектори, так і в комбінації з низькими дозами ДМСО [1,4,12,38,119]. Так, протягом останніх двох десятиліть багато уваги було приділено такому дисахариду, як трегалоза, яка володіє унікальними властивостями: сприяє ефективності формування склоподібного стану льоду, підтримує термодинамічну стабільність клітинних мембран, пригнічує ліпідний фазовий перехід та розділення ліпідів під час заморожування [43,123].…”

“…As various data demonstrate, the minimum dose threshold for a single transplantation is (2.0-3.0) × 10 7 , and for double transplantation it made (1.5-2.0) × 10 7 per kg of the recipient's weight of each of the UCB units [4,39]. In particular, the Eurocord working group does not recommend the use of units, containing less than 3 × 10 7 NCs per 1 kg of the recipient's weight (according to the data obtained before freezing) [40,105].…”