Successful Engraftment and Full Donor Chimerism in Patients Undergoing Second Allogeneic Stem Cell Transplantation with Umbilical Cord Blood

Background: Patients with graft failure or disease relapse following allogeneic hematopoietic cell transplant (HCT) have <10% survival with no intervention. Second HCT in this situation is becoming more common. Advantages of cord blood (UCB) in this setting include prompt availability of donor cells, no donor risk during cell procurement, and potential of enhancing the graft versus leukemia effect through use of highly mismatched grafts. We sought to determine the feasibility of second allogeneic transplant with UCB.

Methods: Twenty-three patients median age 33 yrs (range 4 - 69 yrs) received a CB transplant (CBT) as a second allogeneic HCT at the Fred Hutchinson Cancer Research Center between 2006 – 2013. Indication for second allograft were relapse (n = 19), graft failure (n = 3) and donor derived MDS (n = 1). Median time between transplants was 505 days (range, 55 - 3515). At the time of second HCT, 19 patients were in CR and 4 patients had persistent disease.  For their second transplant, 10 patients received reduced intensity conditioning (RIC) with fludarabine (Flu) 200mg/m², cyclophosphamide (Cy) 50 mg/kg and 200 - 400 cGy TBI, 2 patients received myeloablative (MAC) conditioning with Flu 75mg/m², Cy 120mg/kg and 1200 - 1320cGy TBI (n = 2), and 11 patients received “midi” conditioning with treosulfan 42mg/kg, Flu 150 - 200mg/m² and 200 cGy TBI. All patients received GVHD prophylaxis with cyclosporine and mycophenolate mofeteil. Twenty of the 23 patients received a double CBT with a median TNC of 4.8 x 10⁷ cells/kg and a median CD34+ of 2.2 x 10⁵ cells/kg. Twelve patients received at least one 4/6 graft; 9 patients received at least one 5/6 graft.

Results: Median time to engraftment was 22 days (range day 6 - 49) among 21 evaluable patients; 2 patients died prior to engraftment.  Median time to platelet engraftment was 55 days (range 23 - 83).  Day +28 CD3+ chimerism was 100% second transplant donor in 16 of 19 evaluable patients, and 100% first donor in 2. One patient was mixed between first (22%) and second donor (78%). Death prior to Day 100 was seen in 5 patients (infection/organ failure (n = 3), encephalopathy (n = 1), and relapse (n = 1). Acute grade II-IV and III-IV GVHD was diagnosed in 18 of 21 and 6 of 21 evaluable patients respectively, and 9 of 16 evaluable patients developed chronic GVHD (6 mild, 2 moderate, 1 severe).  Disease free survival, treatment related mortality, and relapse at 2 years was 40%, 33%, and 35% respectively. Patients receiving MAC/midi vs RIC conditioning experienced a 2-year DFS of 46 vs 15% (p = 0.02) and relapse rate of 26 vs 45% (p = 0.20). 

Conclusions: Our results demonstrate quite favorable outcomes in patients undergoing CBT as a second allogeneic HCT, with all evaluable patients engrafting and full donor chimerism achieved in 16 of 19 patients by Day +28. The use of CB as the stem cell source is particularly attractive in this setting as it eliminates the need to put a conventional donor at risk.