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3548 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

Program: Oral and Poster Abstracts
Session: 721. Allogeneic Transplantation: Conditioning Regimens, Engraftment and Acute Toxicities: Poster II
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, ALL, clinical trials, Chemotherapy, pediatric, GVHD, Radiation Therapy
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Christina Peters1,2*, Peter Bader, MD, PhD3, Ulrike Pötschger, PhD2*, M. Akif Yesilipek, MD4*, Herbert Pichler, MD5*, Franco Locatelli, MD, PhD6, Raquel Staciuk, MD7*, Adriana Balduzzi, MD8,9*, Gergely Krivan, MD, PhD10*, Marianne Ifversen, MD11*, Cristina Díaz De Heredia, MD12*, Marc Bierings, MD13, Jacek Wachowiak, MD14* and Jean-Hugues Dalle, MD, PhD15*

1St. Anna Children's Hospital, Vienna, Austria
2Children’s Cancer Research Institute, Vienna, Austria
3Department of Pediatrics, Division for Stem Cell Transplantation, Immunology and Intensive Care, Goethe University Frankfurt, University Hospital, Frankfurt, Germany
4Medical Park Antalya Hospital, Antalya, Turkey
5Children's Cancer Research Institute, St. Anna Children's Hospital, University Vienna, Vienna, Austria
6IRCCS Bambino Gesù Children’s Hospital, Catholic University of the Sacred Heart, Rome, Italy
7Hospital de Pediatría "Prof. Dr Juan P. Garrahan", Buenos Aires, Argentina
8Department of Medicine and Surgery, Milano-Bicocca University, Milano, Italy
9Pediatric Hematopoietic Stem Cell Transplant Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
10Pediatric Hematology and Stem Cell Transplantation Department, National Institute of Hematology and Infectious Diseases, Central Hospital of Southern Pest, Budapest, Hungary
11Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
12Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca, Barcelona, Spain
13Princess Máxima Center, University Hospital for Children, Utrecht, Netherlands
14Department of Pediatric Oncology, Hematology and Transplantology, Poznań University of Medical Sciences, Poznan, Poland
15Pediatric Hematology and Immunology Department, GHU APHP Nord - Université Paris Cité, Robert Debré Hospital, Paris, France


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, >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.


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 > 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 > 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 > 14 years, in 98 pts transplanted in first CR vs. > 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. >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).


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 > 14 years compared to younger patients.

Disclosures: Peters: Amgen, Jazz, Neovii: Research Funding; Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees; AOP Orphan Drugs, Jazz, Neovii: Other: Support for attending meetings and/or travel; Novartis: Consultancy; Medac, Riemser: Honoraria. Bader: Novartis: Consultancy, Research Funding; Neovii: Research Funding; BMS: Research Funding; Medac: Consultancy, Patents & Royalties: medac, Research Funding. Pichler: Neovii: Other: Travel grants . Balduzzi: Novartis, Amgen, Medac, Neovii: Speakers Bureau. Díaz De Heredia: Biotest: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: travel expenses; Prothya Biosolutions: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: travel expenses, Speakers Bureau. Dalle: blue bird bio, Incyte, Jazz Pharm. Medac, Sanofi, Vertex: Membership on an entity's Board of Directors or advisory committees; Novartis, Orchard: Membership on an entity's Board of Directors or advisory committees, Other: speaker (symposia).

*signifies non-member of ASH