Reduced Intensity Allogeneic Transplant in Patients Older Than 55 Years: Unrelated Umbilical Cord Blood Is Safe and Effective for Patients without a Matched Related Donor.
Authors: Majhail Navneet S. , Brunstein Claudio , Wagner John E. , Tomblyn Marcie , Thomas Avis , Miller Jeffrey S. , Arora Mukta , Kaufman Dan S. , Burns Linda J. , Slungaard Arne , McGlave Philip B. , Weisdorf Daniel J. 
Published: October 2019

Abstract
The lower morbidity and mortality of reduced-intensity conditioning (RIC) regimens has allowed allogeneic hematopoietic cell transplantation (HCT) in older patients. Unrelated umbilical cord blood (UCB) has been investigated as an alternative stem cell source because of insufficient availability of suitably HLA matched related (MRD) and adult volunteer unrelated donors. We hypothesized that RIC HCT using UCB would be safe and efficacious in older patients and compared the transplant related mortality (TRM) and overall survival (OS) after RIC HCT in patients older than 55 years using either MRD (n=47) or, in patients with no 5/6 or 6/6 HLA compatible related donors, UCB (n=43). RIC regimen consisted of total-body irradiation (200 cGy) and either cyclophosphamide and fludarabine (n=69), or busulfan and fludarabine (n=16) or busulfan and cladribine (n=5). The median age of MRD and UCB cohorts was 58 (range, 55–70) and 59 (range, 55–69) years, respectively. AML/MDS (50%) was the most common diagnosis. All MRD grafts were 6 of 6 HLA matched to the recipient. Among patients undergoing UCB HCT, 38 (88%) received two UCB units to optimize cell dose and 40 (93%) received 1–2 HLA mismatched grafts. The median total nucleated cell dose was 9.2 × 108/kg (range, 3.0–21.2) for MRD grafts and 0.4 × 108/kg (range, 0.2–0.8) for UCB grafts. The median followup for survivors was 27 (range, 12–61) months. The probability of progression-free survival (PFS) at 3-years for recipients of MRD and UCB was 30% (95% confidence intervals [CI], 16–44%) and 34% (95% CI, 19–48%)(p=0.98) and OS was 43% (95% CI, 29–58%) and 34% (95% CI, 17–50%)(p=0.57), respectively. The cumulative incidence of sustained donor engraftment at 6 weeks was 100% for MRD and 89% (95% CI, 80–99%) for UCB recipients (p=0.05). The cumulative incidence of grade 2–4 acute graft-versus-host disease (GVHD, 42% vs. 49%, p=0.20) and TRM at 180-days (23% vs. 28%, p=0.36) was comparable between the MRD and UCB groups; however, UCB recipients had a lower incidence of chronic GVHD at 1-year (40% vs. 17%, p=0.02). On multivariate analysis, graft type (MRD vs. UCB) had no impact on TRM, PFS or OS; only HCT comorbidity index score was independently predictive for these endpoints. For the whole cohort, 180-day TRM for patients with HCT comorbidity index scores of 0, 1–2 and ≥ 3 was 14% (95% CI, 0–28%), 19% (95% CI, 5–32%) and 44% (95% CI, 26–62%), respectively. Compared to patients with a higher score, patients with a score of 0–2 had lower TRM (hazard ratio [HR] 0.3 [95% CI, 0.1–0.7]) as well as better PFS (HR 0.5 [95% CI, 0.3–0.9]) and OS (HR 0.5 [95% CI, 0.2–0.9]). Our study supports the use of HLA mismatched UCB as an alternative graft source for older patients who need a transplant but do not have a MRD. The use of RIC and UCB extends the availability of transplant therapy to older patients previously excluded on the basis of age and lack of a suitable MRD. Older HCT candidates with limited comorbidity have a low and acceptable risk of TRM and a careful review of existing comorbidities is necessary when considering older patients for HCT.