Similar Overall Survival and Event-Free Survival for Patients Under or over the Age of 14 Years, but More Chronic Graft Versus Host Disease and Non-Relapse Mortality in the “Older” Patients
Authors: Peters Dr. , Bader Peter , Pötschger Ulrike , Yesilipek M. Akif , Pichler Herbert , Locatelli Franco , Staciuk Raquel , Balduzzi Adriana , Krivan Gergely , Ifversen Marianne , Díaz De Heredia Cristina , Bierings Marc , Wachowiak Jacek , Dalle Jean-Hugues 
Published: December 2023

Purpose:
In the prospective, randomized, multinational FORUM trial, total body irradiation and etoposide were statistically more effective than chemoconditioning (Peters et al, JCO 2021; FORUM study; EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129). The multivariate analysis in this cohort showed an inferior overall survival (OS) for patients (pts) over the age of 10 years, HR 1.8 (95% CI, p=0.048). To update these findings, we examine the impact of age at allogeneic hematopoietic stem cell transplantation (HSCT), we analyzed 791 FORUM pts who received TBI and etoposide as conditioning regimen between April 2012 and March 2022 and compared their outcomes according to different age categories.
Patients and Methods:
Almost all patients were transplanted in second or first complete remission (CR2) (47%, n=370; CR1: 46%, n=361, &gt;CR3: 8%, n=59), from matched unrelated donors (MUD) 70%, n=552, HLA-identical sibling donors (MSD) 30%, n=239, bone marrow (BM) 70%, n=551, or cord blood (CB) 3%, n=26. Median age at HSCT was 10 years (4-21). Median observation time was 2.3 years (0.3 to 8) (Table 1: Basic Characteristics). The conditioning regimen consisted of total body irradiation (TBI) - 6 fractions of 2 Gy on 3 consecutive days followed by 60 mg/kg body weight etoposide (max 1800 mg/m2, total upper dose limit 3.6 g). GVHD prophylaxis was CSA only for MSD receiving bone marrow. ATG/CSA/MTX was used for the MUD HSCT group.
Results:
127 evaluable pts were transplanted between 4-6 years (group 1), 249 between 6-10 years (group 2), 231 between 10-14 years (group 3), and &gt; 14 years were 184 pts (group 4) (n.s.) By the 4 age groups, the 5-year OS was 0.83±0.04 (group 1), 0.75±0.04 (group 2), 0.75±0.04 (group 3), and 0.74±0.04 (group 4), respectively, p = 0.133. Five-year event-free survival (EFS) was also similar for all age groups: 0.71 ± 0.06, 0.72 ± 0.04, 0.66 ± 0.05, 0.69 ± 0.04 (p=0.611): Figure 1. The three-year cumulative relapse incidences (CIR) were 0.23±0.04, 0.19±0.03, 0.14±0.03, and 0.17±0.03, respectively (p=0.286). Non-relapse mortality (NRM) was significantly lower in the two younger age groups (0.02 ± 0.01 group 1 and 0.05 ± 0.02 group 2) compared to 0.11 ± 0.02 in both older age groups (p = 0.047). The primary causes of death in the 18/184 pts in group 4 were as follows: infections (fungal, viral, bacterial): n=8, acute and chronic graft versus host disease (aGVHD, cGVHD): n=3, sinusoidal obstruction syndrome, coagulopathies: n=4, multi-organ failure: n=3. Among the 767 evaluable pts, 503 (66%) had no or grade1 aGVHD, 188 (25%) had grade 2 aGVHD, and 76 pts (11%) had grade3 to 4 aGVHD; in patients &gt; 14 years 22 (14%) had a grade 3 to 4 aGVHD (p = 0.624). The 3-year incidence of extensive cGVHD was significantly higher in pts older than 14 years (0.21±0.03 vs. 0.10±0.03, 0.11±0.02 and 0.14±0.03, respectively), which also translated into significantly better extensive cGVHD-free, relapse-free survival (cGRFS) for the younger cohorts (Table 1). To date, the overall incidence of secondary malignancies in this cohort is 0.01 (n = 11) with no significant differences in the 4 age categories.
In the age group &gt; 14 years, in 98 pts transplanted in first CR vs. &gt; CR1 (n=86), 5-year OS is 0.83±0.04 and 0.63±0.06, respectively (p=0.005). Similarly, 5-year EFS was 0.79±0.05 and 0.56±0.07, respectively (p=0.002). In multivariate analysis, OS, EFS, CIR was not influenced by donor type and pts' age at transplant. However, NRM was higher in pts older than 14 years, the hazard ratio (HR) being 4.8 (1.4-16; p=0.012) as compared to patients aged 4-6 years. Remission status (CR1 vs. &gt;CR1) had significant impact on EFS with HR of 1.6 (1.1-2.1; p= 0.004) and CIR (HR 1.7; 1.1-2.4; p= 0.012).
Conclusions:
In the FORUM trial, patients who underwent allogeneic HSCT from HLA-identical or HLA-matched unrelated donors older than 4 years and younger than 21 years who received myeloablative conditioning with TBI/etoposide had similar overall and event-free survival regardless of age at HSCT. The incidence of chronic GVHD and NRM was higher in patients &gt; 14 years compared to younger patients.