Complementary Transplantation with Haploidentical Stem Cells and Unrelated Cord Blood in Thalassemia Major

Abstract

▪BackgroundEffects of haploidentical stem cells (Hap-SC) and unrelated cord blood (UCB) transplant are unsatisfactory in thalassemia major (TM) so far. High rejection and low TM-free survive (TFS) were key clinical issues. Increased rejection often offset the effort of lowered GVHD. The effect of alloreactive clone destruction in post-transplant cyclophosphamide (Cy, PTCy) transplant resulted in low GVHD and high relapse but nice immuno-recovery and immuno-tolerance by keeping antivirus and regulatory T cells. These may just complement the congenital insufficiency, delay engraftment and slow immuno-recovery, of UCB transplantation. Conversely, graft vs. leukemia effect and controllable GVHD from naive T cells of UCB offset the lack above of hap-SC transplant with PTCy. Therefore, we developed a novel complementary transplant with Hap-SC and UCB (CT-hap-CB) for leukemia and TM patients.Patients and methodThirty-six TM patients received CT-hap-CB between December 2013 and June 2016. Median age was 8 (range, 3-24) years old. Median follow-up time was 19 (2-25) months. Conditioning (Regimen, CT-13) included Cy on day-8 to -7, Busulfan on day-6 to -4, Fludarabine on day-6 to -2 and Thiotepa on day-3. GVHD prophylaxis consisted of Cy on day+3 to +4, Mycophenolate mofetil and Tacrolimus from day+6. Noteworthily, UCB was infused on day+6. The latter 26 TM patients received additionally Thymoglobuline on day -11 to -9 (Regimen, CT-14).ResultsPreponderance engraftment of hap-SC, UCB, mixed stem cells (MSC) and rejection in16, 14, 3 and 3 patients, respectively, at the last follow-up. Initial (day+28) full hap-SC, UCB and MSC chimerism occurred in 15, 7 and 12 patients. Cells derived from UCB overtime were dominant instead of initial majority from hap-SC (Fig. 1) in MSC group. 7/10 UBS with centromeric B motif engrafted.Median times to neutrophil ≥ 0.5x109/L, platelet ≥ 20 x109/L and hemoglobin ≥ 80 g/L were day+20.0 (range; 14-47), 11.0 (9-162) and 11 (1-39); 47.0 (34-113), 66.0 (12-227) and 46.0 (13-63); and 24 (1-46), 14 (11-116) and 8 (4-91), respectively, in initial hap-SC (n, 15), UCB (n, 7) and MSC (n, 12) groups. Overall survive, thalassemia free survive (TFS), rejection and mortality related transplant were 91.2%, 85.7%, 5.6% and 8.8%, respectively. Impressively, all of the 26 patients who received CT-14 protocol were alive without TM (Fig. 2). Grade II, III and IV acute GVHD occurred in 3 patients, respectively. One patient died of grade IV GVHD and another died of infection when the parents abandoned therapy after rejecting graft. Chronic GVHD was mild and rare.SummaryCT-hap-CB resulted in high OS and TFS, especially CT-14 leaded to 100% TFS with low GVHD rate. MSC engraftment improved hematopoietic recovery of UCB. KIR and HLA typing impacted what stem cells engraftment. The multicenter study should be developed in the future. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.