Double-Unit Cord Blood (CB) Transplantation (DCBT) Combined with Haplo-Identical CD34+ Selected Peripheral Blood Stem Cells (PBSC) Is Associated with Enhanced Neutrophil Recovery, Universal Haplo Rejection and Frequent Pre-Engraftment Syndrome
Authors: Sanchez Matias Eugenio , Ponce Doris M. , Lauer Emily J , Lubin Marissa N , Barone Jonathan , Byam Courtney , Dahi Parastoo B , Meagher Richard , Castro-Malaspina Hugo , Jakubowski Ann A. , Koehne Guenther , Papadopoulos Esperanza B , Perales Miguel-Angel , Sauter Craig S. , Tamari Roni , Scaradavou Andromachi , Kernan Nancy A. , Giralt Sergio , O'Reilly Richard J , Barker Juliet N. 
Published: October 2019

Abstract

Introduction While DCBT provides high rates of sustained donor engraftment, delayed neutrophil recovery is frequent and associated with increased transplant-related mortality.
Methods We are investigating the combined transplantation of a 4-6/6 double-unit CB allograft with CD34+ selected haplo-identical PBSC (haploCD34+) to speed myeloid recovery in patients (pts) with high-risk hematologic malignancies. This analysis evaluates sustained neutrophil recovery, engraftment patterns, and potential factors associated with haplo-rejection in 36 DCBT-haploCD34+ recipients.
Results 36 DCB-haplo-CD34+ pts (median 48 years, range 16-69) were transplanted 9/2012-6/2014. Diagnoses included 28 acute leukemias (24 CR or aplasia, 4 not in CR) and 8 advanced lymphoid malignancies. 2 pts had had a prior allograft. Conditioning was myeloablative (2 high-dose TBI, 34 reduced intensity) with CSA/MMF and no ATG. CB units had a median infused TNC (x 107/kg) of 2.26 (larger unit) & 1.87 (smaller unit), & a median HLA-allele match of 5/8 (range 2-7/8). Haplo-identical donors (median 37 years, range 18-71) had a median HLA-match of 4/8 (range 4-6/8). The median infused haplo-CD34+ dose was 3.1 x 106/kg (range 1.1-7.5). The median infused haplo-CD3+ dose was 1.5 x 103/kg (range 0.3-8.0). One patient died early post-transplant (multiorgan failure). In 35 evaluable pts, engraftment patterns [groups (Gp) 1-4] based on count recovery & chimerism are shown (Table). Overall, 34/35 (97%) pts recovered neutrophils (median day 13, range 11-38) whereas one 2nd allograft pt with donor-specific HLA-Abs (DSA) to haplo & both units had both primary haplo-rejection and CB graft failure (GF, Gp 4). Additionally, one pt (Gp 4) with transient haplo-mediated neutrophil recovery had subsequent CB GF in the setting of low CD34+ dose in the dominant unit. Both GF pts were salvaged with single-unit CBT. In other pts, haplo-rejection was universal & was associated with dominant CB unit derived T-cell engraftment although rejection speed varied, low haplo dose may have contributed in 2 pts, and 3 of 4 pts overall with haplo-DSA had no haplo-engraftment.
Table Engraftment Pattern(n = 35) Median (range)Haplo DoseCD34+ x 106/kg Median (range) 8 Allele HLA-match: Haplo-PatientHaplo-Dominant CB N with DSAto Haplo/ CBs Median (range)Dominant CB CD34+ Dosex 105/kg 1) CB engraftment with haplo bridge (no recurrent neutropenia) N = 18 (51%) Median ANC 12 days, (range 11-14) 3.14 (2.86-5.62) Haplo-patient: 4/8 (4-6/8) Haplo-dom. CB: 4/8 (range 1-7/8) 1 pt DSA to haplo 1 pt DSA to loser CB 1.14 (0.37-5.66) 2) CB engraftment with transient haplo (2nd nadir) N = 5 (14 %) Median ANC 14 days, (range 11-38) 3.0 (2.56-7.46) Haplo-patient: 4/8 (all 4/8) Haplo-dom. CB: 2/8 (2-4/8) None 0.46 (0.25-1.00) 3) CB engraftment with no haplo N = 10 (29%) Median ANC 26 days, (range 15-33) 3.00 (1.05-5.29) Haplo-patient: 4/8 (4-5/8) Haplo-dom. CB 3/8 (1-4/8) 2 pts DSA to haplo 1 pt DSA to loser CB 0.85 (0.54-1.39) 4) Graft failure N = 2 (6%) Pt 1: transient haplo/ no CB Pt 2: no haplo/ no CB Pt 1: 5.06 Pt 2: 4.64 Haplo-patient: Pt 1: 4/8. Pt 2: 5/8 Haplo-dom. CB: Pt 1: 4/8. Pt 2: 4/8 Pt 2: DSA to haplo, dom. CB & losing CB Pt 1: 0.22 Pt 2: 1.27
Of 35 evaluable pts, 27/35 (77%) developed pre-engraftment syndrome (PES, fever >38.3°C not due to infection +/- rash, capillary leak) at a median 10 day onset (range 7-14). PES occurred in 11/18 (61%) Gp 1 pts with robust haplo myeloid bridge vs 16/17 (94%) Gp 2-4 pts with rapid haplo-rejection. Overall, 3/27 (11%) PES pts required ICU care although marked improvement was associated with corticosteroids.
Conclusions: DCBT-haploCD34+ is feasible & neutrophil engraftment is enhanced. However, given the haplo-graft can be rapidly rejected, and sustained engraftment is not guaranteed, the quality & dose of the CB unit(s) in this platform is critical. Preliminary analysis suggests the haplo-graft dose & haplo-DSA may be relevant in haplo engraftment whereas there is a high degree of dominant CB unit-haplo HLA-mismatch and its role is unclear. Finally, PES may be more common with prompt haplo-rejection, may be clinically severe, and mandates early diagnosis and pulse corticosteroids. Analysis of serial cytokine samples to further investigate PES biology is ongoing.

Disclosures
No relevant conflicts of interest to declare.