The Fountain of Youth: Outcomes of Nonmyeloablative (NMA), HLA-Haploidentical Related (Haplo) Bone Marrow Transplantation (BMT) with Post-Transplantation Cyclophosphamide (PTCy) Best with Younger Donors Regardless of Relationship to Patient
Authors: Franklin Clio E , Showel Margaret M. , Tsai Hua-Ling , Varadhan Ravi , McCurdy Shannon R. , Gladstone Douglas E. , Jones Richard J. , DeZern Amy E. 
Published: April 2021

Abstract

NMA haplo BMT with PTCy is an increasingly used therapeutic strategy in patients with hematological malignancies (HM). Data demonstrating the safety of this NMA approach in older patients has led to an increased percentage of BMT performed in patients aged &gt; 60 years. Consequently, the average age of potential related donors to be evaluated is also increasing. We sought to determine if donor age and donor relationship to the patient affected outcomes in patients undergoing NMA haplo BMT with PTCy.
We retrospectively evaluated 586 adult and pediatric patients with HM who underwent NMA haplo BMT with PTCy from October 2002 through 2015. All patients received NMA conditioning with fludarabine, Cy, and total body irradiation, followed by allografting bone marrow stem cells from a first-degree relative. Graft-versus-host disease (GVHD) prophylaxis consisted of two doses of high-dose PTCy, mycophenolate mofetil and either sirolimus or tacrolimus. Donor age range was categorized into &lt;30 years, 30-45 years and &gt;45 years. Patients not receiving their first allogenic BMT were excluded.
The median patient age was 57 years (range 1-76) and 63% were male. The indication for BMT was AML in 163 patients (27.8%), MDS in 34 (5.8%), MPN in 7 (1.2%), ALL in 52 (8.9%), CML in 15 (2.6%),CMML in 6 (1.0%), biphenotypic leukemia in 6 (1.0%), aggressive B cell lymphoma (BCL) in 94 (16.0%), T cell lymphoma in 36 (6.1%), mantle cell lymphoma in 31 (5.3%), Hodgkin's lymphoma in 54 (9.2%), indolent BCL in 34 (5.8%), CLL in 33 (5.6%), multiple myeloma in 13 (2.2%) and other HM in 8 (1.4%). Donor age ranged from 13-79 years. Donors were divided into three age categories: 146 of donors were &lt;30 years (24.9%), 231 were 30-45 years (39.4%) and 209 were &gt;45 years (35.7%). The most common donor relationship to the patient was children (83.6%) from donors &lt;30 years, children (69.7%) from donors 30-45 years and siblings (56.9%) from donors &gt;45 years. There was no correlation between donor and recipient age, with the older patients having the youngest donors and vice versa (Figure 1). Disease Risk Index score (DRI) was low in 90 patients (15.4%), intermediate in 368 (62.8%), high/very high in 94 (16.0%) and not determined in 34 (5.8%). Median follow-up was 2.9 years (range 9 days-11.4 years). Median CD34 infused was 4.61x106/kg from donors &lt;30 years, 4.11x106/kg from donors 30-45 years and 3.62x106/kg from donors &gt;45 years (p=0.0001). Younger donors were associated with lower non-relapse mortality (NRM); on competing-risk analysis, the cumulative incidence of NRM was 6% (95% CI 2−10%) at 3 years in patients with donors &lt;30 years, 16% (95% CI 11−22%) in patients with donors 30−45 years and 15% (95% CI 10−20%) in patients with donors &gt;45 years (p=0.02, Figure 2A).
The probability of progression free survival (PFS) at 3 years was 45% (95% CI 37−55%) in patients with donors &lt;30 years, 37% (95% CI 30-44%) 30-45 years and 37% (95% CI 31−45%) &gt;45 years (p=0.23). The probability of overall survival (OS) at 3 years was 61% (95% CI 52−71%) in donors &lt;30 years, 49% (95% CI 42−57%) 30-45 years, and 49% (95% CI 43−57%) &gt;45 years (p=0.08, Figure 2B). The donor relationship did not influence outcomes with the probability of PFS at 3 years 40% (95% CI 30−54%) with parental donors, 39% (95% CI 32−47%) with sibling donors, and 39% (95% CI 33−45%) in child donors (p= 0.99). The probability of OS at 3 years was 53% (95% CI 42−67%) with parental donors, 51% (95% CI 44−59%) with sibling donors and 52% (95% CI 46−59%) in child donors (p= 0.97).
These results confirm the benefit of using donors &lt;30 years of age for NMA haplo BMT with PTCy. This adds to the increasing evidence that donor age is a universal risk factor in BMT. Although reasons for this association have been suggested (i.e. a higher proportion of memory T cells in older donors), this requires further analysis. The data also illustrate that the donor's relationship to the patient (i.e. sibling, child or parent) had no significant impact on NRM, OS, or PFS. With this transplantation platform, the youngest haplo relative, regardless of their relationship to the patient, should be considered the preferred donor source for patients in need of BMT. Since previous analyses have shown no difference between haplo with PTCy and matched sibling donor (MSD) BMT, consideration should be given to selecting a younger haplo donor over an older MSD; however, further work in this area is needed before adopting such a strategy widely.

Disclosures
No relevant conflicts of interest to declare.