Important Prognostic Impact of Early Monocytes Recovery after Reduced Intensity Conditioning Double Umbilical Cord Blood Allogeneic Stem Cell Transplantation in Adults
Authors: Le Bourgeois Amandine , Guillaume Thierry , Delaunay Jacques , Peterlin Pierre , Dubruille Viviane , Mahe Beatrice , Blin Nicolas , Gastinne Thomas , Voldoire Maud , Duquesne Alix , Le Gouill Steven , Moreau Philippe , Mohty Mohamad , Campion Loic , Chevallier Patrice 
Published: October 2019

Abstract
Introduction: Little is known regarding the impact of hematopoietic and immune recoveries after double umbilical cord blood (dUCB) allogeneic stem cell transplantation (allo-SCT), especially after the TCF (low dose 2 Grays total body irradiation + cyclophosphamide 50 mg/Kg 1 day + fludarabine 200 mg/m² 5 days) reduced-intensity conditioning (RIC) regimen, which is considered as a standard RIC regimen for dUCB allo-SCT in adults
Patients and Methods: Here we considered a homogeneous cohort of 47 patients (males: n=24; median age: 55.5 years (range: 17.5-69) who engrafted after a dUCB TCF allo-SCT performed between November 2006 and April 2013 in our department. Fifty-three percent of the patients had myeloid disease. The majority of cases were in complete remission at time of transplant (72.3%). GVHD prophylaxis consisted of cyclosporine + mycophenolate mofetyl in all cases. All patients received G-CSF from day 1 until neutrophils recovery. The median nucleated cells dose infused was 4.17 107/kg. The aim of the study was to investigate the impact on outcomes of the recovery of the following cellular subsets: leucocytes, monocytes, lymphocytes, neutrophils at day +30 and day +42, and CD4+, CD8+ T cells, B and NK cells at day+100.
Results: Median times for neutrophils and platelets recoveries were 17 days (range: 6-59) and 37 days (range: 0-164), respectively. With a median follow-up of 30.4 months (range: 2.8-77.5), the 3-year overall and relapse-free survivals (OS, RFS), relapse incidence (RI), and non-relapse mortality (NRM) were 65.7%, 57.2%, 27.1% and 19%, respectively. The cumulative incidences of grade II-IV and grade III-IV acute GVHD were 38.3% and 10.6%, respectively, while, 3-year incidence of chronic GVHD was 53.5% (limited 42%, extensive 11.5%).
In univariate analysis, 3-year OS was significantly higher in case of lymphoid disease (80.9% vs 51.9%, p=0.05) or when achieving at day+30 or day +42 higher counts of leucocytes (> median: 2760/mm3; 79% vs 51%, p=0.05; median > 4250/mm3; 78.6% vs 55.4%, p=0.04) or monocytes (> median: 615/mm3; 87.5% vs 45.8 %, p=0.02; median > 830/mm3, 86.2% vs 54.1%, p=0.03). Older age (>median: 55 years) and higher monocytes count at day +42 (> median: 830/mm3) were significantly associated with higher 3-year RFS (63.6% vs 49.1 %, p=0.046; and 75.7 vs 44.4%, p=0.014). Higher leucocytes count at day +42 (>median: 4250/mm3) was the only factor associated with significant 3-year lower NRM (7.1% vs 31.7%, p=0.04), while younger age was associated with higher risk of grade 3-4 acute GVHD (16.7% vs 4.4 %, p=0.05). No factor was predictive of chronic GVHD in this series.
In multivariate analysis, older age and early higher monocytes count after transplant were the two independent factors associated with a significantly higher OS (>55 years, HR: 0.21; 95%CI: 0.05-0.85, p=0.028; >615/mm3 at day +30, HR: 0.05; 95%CI: 0.01-0.43, p=0.006) while only older age remained independently associated with better RFS (>55 years, HR: 0.25, 95%CI: 0.08-0.78, p=0.017). No factor was predictive of NRM, grade 2-4 GVHD, grade III-IV acute or chronic GVHD.
Conclusion: These results suggest that higher early monocytes recovery is predictive of outcome after dUCB TCF RIC allo-SCT in adults. Immune recovery seems to have no impact on survivals in this series while influence of age has to be confirmed by other studies. Our results pave the way for future studies aiming to closely and prospectively monitor the kinetics of hematopoietic and immune recoveries after this type of graft. As all patients received G-CSF after transplant, other immunostimulatory cytokines should be tested to ensure sufficient hematopoietic recovery in the setting of adult dUCB TCF RIC allo-SCT.

Disclosures
No relevant conflicts of interest to declare.