Double-Unit Cord Blood (CB) Transplantation (DCBT) Combined with Haplo-Identical Peripheral Blood CD34+ Cells (HaploCD34+) Is Associated with Enhanced Neutrophil Recovery, Universal Haplo Rejection, and Frequent Pre-Engraftment Syndrome

Introduction: Delayed neutrophil recovery after myeloablative DCBT (median 25 days in adults) is frequent & associated with prolonged hospitalization & increased transplant-related mortality. Methods: We investigated DCBT combined with haploCD34+ cells to speed myeloid recovery. Results: Between 9/2012-8/2014 16/55 (29%) eligible patients (pts) could not receive DCBT-haplo as they had no haplo (n = 10) or had no CB ± no haplo graft (n = 6). 39 pts (median 48 years, range 15-68) with high-risk hematologic malignancies [30 acute leukemias (25 morphologic CR or aplasia, 5 not in CR) & 9 advanced lymphomas] underwent DCBT-haploCD34+ after myeloablation (2 high-dose Cy/Flu/TBI-1375, 37 reduced intensity Cy/Flu/Thio/TBI-400) with CSA/MMF & no ATG. CB units had a median infused TNC x 10⁷/kg of 2.30 (larger unit) & 1.86 (smaller unit), & a median donor-recipient HLA-allele match of 5/8 (range 2-7/8). Haplo-donors (median 37 years, range 15-71) had a median 4/8 (range 4-6/8) donor-recipient HLA-match. The median infused haploCD34+ cell dose was 3.1 x 10⁶/kg (range 1.1-7.5) & CD3+ cell dose was 1.5 x 10³/kg (range 0.3-13.7). One pt died early post-transplant. In 38 evaluable pts, 37/38 (97%) recovered neutrophils (median day 13, range 11-38) whereas 1/38 with donor-specific HLA-Abs (DSA) to the haplo & both CB units had haplo/CB rejection. Additionally, one of the 37 pts with early neutrophil recovery had haplo rejection & CB graft failure in the setting of very low dominant CB unit CD34+ cell dose. The remaining 36 pts had both sustained CB engraftment & universal haplo-rejection as follows (examples in Figure): 20/36 (56%) pts had a haplo-bridge without recurrent neutropenia (Fig. A), 5/36 (14%) had transient haplo-engraftment with second nadir (Fig. B), & 11/36 (30%) had no haplo-engraftment & delayed CB-mediated neutrophil recovery (median 26 days, range 15-33, Fig. C). Haplo rejection & sustained CB engraftment was associated with dominant unit-derived peripheral blood T-cells (detected day +28). There was no association between the haplo-bridge duration & the haploCD34+ cell dose (above a dose of 2.0 x 10⁶/kg) or the haplo-dominant CB unit HLA-match (median 3/8). 29/38 (76%) pts developed pre-engraftment syndrome (PES, median onset day 10, range 7-15). PES was severe in 3/38 (8%) pts but all resolved with corticosteroids. Conclusions: DCBT-haploCD34+ is feasible in most pts & neutrophil engraftment is enhanced. However, the haplo-bridge is not guaranteed & given the haplo-graft can be rapidly rejected the quality & dose of the CB unit(s) is critical. Low haplo-graft dose & haplo-DSA are likely relevant in haplo engraftment whereas the dominant CB unit-haplo HLA-mismatch is not (possibly due to the high degree of mismatch observed between all haplo & CB grafts). Finally, PES is common after DCBT-haplo, may be severe, & requires early corticosteroid therapy.