Relapse Is the Most Common Treatment Failure Post HSCT in Children with ALL below 4 Years of Age Given a Chemo-Based Conditioning Regimen. Results from the Prospective Multinational Forum-Trial

Background: Relapse and non-relapse mortality (NRM) are the major causes of treatment failure in infants and young children with high-risk ALL undergoing HSCT. Conditioning regimens for this high-risk population usually omit total body irradiation (TBI) to avoid acute and long-term side effects that are more pronounced in this age group. The optimal chemotherapeutic approach aiming improved event-free survival (EFS) and low NRM is not yet defined.

Methods: The prospective FORUM trial used two myeloablative chemo-conditioning regimens for children <4 years (yrs) of age: fludarabine (FLU), thiotepa (THIO) and either intravenous busulfan (BU) or treosulfan (TREO) as described previously (Peters et al., JCO 2021). This report includes 194/202 patients (pts) (107 male, 87 female) from 26 countries enrolled in FORUM who received HSCT (5 pts received TBI-based conditioning and 3 pts with unknown conditioning were excluded). Median age at HSCT was 2.2 yrs (6 months - 4 yrs; 38 pts 0-1yrs (20%), 53 pts 1-2yrs (27%), 53 pts 2-3yrs (27%), 50 pts 3-4yrs (26%)). Stem cell source was bone marrow in 132 (68%) pts, peripheral blood stem cells in 37 (19%), and cord blood in 24 (13%). Donors were HLA-matched siblings (MSD) in 39 (20%) pts and 9 or 10/10 HLA allele-matched unrelated donors (MUD) in 155 (80%) pts.Clonal genetic abnormalities reported at diagnosis included 9 pts with BCR-ABL, 13 pts with TEL-AML, and 53 pts with KMT2A r-rearrangements; all pts underwent HSCT in complete morphological remission (CR) (142 pts CR1; 50 pts CR2, 2 pts CR3). FLU/THIO/BU and FLU/THIO/TREO were used in 101, and 93 HSCTs, respectively. Graft-versus-host-disease (GvHD)-prophylaxis was Cyclosporin-A-based in 90%; recipients of MUD-grafts also received ATG and 3 doses of methotrexate. At data cut-off, median follow-up (FU) was 3 yrs (range, 3 months - 7.2 yrs).

Results: 3-yrs OS was 0.69±0.04, 3-yrs EFS was 0.52±0.04; 3-yrs Cumulative incidence of relapse (CIR) was 0.44+0.04, and 3-yrs NRM was 0.05 ± 0.02. OS and EFS did not differ between pts < 2 and 2-4 yrs of age at HSCT (Table 1). Pts transplanted in CR 1 had significantly better EFS (0.58±0.04) as compared to >CR1pts (0.36±0.07, p=0.01); due to a higher CIR. OS was worse for the 53 pts with KMT2A-rearrangements (3-yrs OS 0.56±0.08 vs. 0.73±0.04, p=0.040). EFS for pts < 1 yr of age at diagnosis was significantly inferior as compared to older pts (3-yrs EFS 0.40±0.05 vs. 0.63±0.05, p=0.002). OS/EFS were not significantly different when donor type, stem cell source, and immunophenotype were compared (Table 1). At 3-yrs, OS was 0.63±0.05 and 0.76±0.05 and EFS was 0.52±0.05 and 0.51±0.06 (p=0.794) for the FLU/THIO/BU and FLU/THIO/TREO-group, respectively (p=0.075) with no significant difference in CIR and TRM. However, pts who relapsed post-HSCT had a better 3-yr post-relapse OS after FLU/THIO/TREO compared to FLU/THIO/BU (0.38±0.11; 0.16±0.07. p = 0.012) respectively. Most relapses occurred prior to 1 yr after HSCT. Acute GVHD occurred in 32 pts (20 pts experienced grade III/IV) with no significant difference between the two conditioning regimen). The 3-yr incidence of chronic GVHD (cGVHD) was comparable between the BU- and -TREO-group (p = 0.943). cGVHD/relapse-free survival at 3 yrs for FLU/THIO/BU was 0.44±0.05 and for FLU/THIO/TREO 0.41±0.06 (p=0.943).

In multivariate analysis, remission > CR1 and the presence of KMT2A, negatively influence OS while EFS was worse for patients who underwent HSCT > CR1 or had ALL-diagnosis below 1 yr of age. Donor type, stem cell source, age between 1 and 4 yrs at HSCT, conditioning regimen, and PCR-MRD positivity pre-HSCT did not significantly influence outcome. 1-yr TRM was low for both conditioning regimens (0.06±0.02 for FLU/THIO/BU and 0.03±0.02 after FLU/THIO/TREO (n.s.)

Conclusion: Within the FORUM-trial, infants and young children receiving HSCT after conditioning with either BU- or TREO containing regimens have a lower OS and EFS as compared to children above the age of 4 yrs due to a higher CIR. Because of decreased NRM, these results represent an improvement as compared to previously reported series; however, KMT2A-rearrangement continues to be an obstacle to successful HSCT. Pre- and post-transplant immunotherapeutic strategies aimed at reducing relapse-incidence without increasing chemotherapy-associated complications are needed.

Figure 1: 3-yrs OS according to Conditioning

Flu: fludarabine, Thio: thiotepa, Treo: treosulfan, Bu: busulfan

Peters:Riemser: Consultancy, Speakers Bureau; Jazz: Other, Research Funding; Neovii: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medac: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dalle:Vertex: Honoraria; Jazz Pharmaceuticals: Honoraria; Medac: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; Teva: Current equity holder in private company; Orchard: Honoraria. Locatelli:NOVARTIS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANOFI: Membership on an entity's Board of Directors or advisory committees; MILTENYI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MEDAC: Speakers Bureau; TAKEDA: Speakers Bureau; SOBI: Speakers Bureau; NEOVII: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BLUEBIRD BIO: Speakers Bureau; JAZZ PHARMACEUTICALS: Speakers Bureau; PFIZER: Membership on an entity's Board of Directors or advisory committees; GILEAD: Speakers Bureau; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Güngör:Novartis: Research Funding; Jazz: Research Funding; Forge Biologics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ifversen:Novartis: Membership on an entity's Board of Directors or advisory committees. Shaw:Novartis: Consultancy; Sanofi: Consultancy. Büchner:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bader:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Medac: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Riemser: Research Funding, Speakers Bureau; Neovii: Research Funding; Bristol Myers Squibb: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Miltenyi: Speakers Bureau.

90% of drugs used in children are off-label. Study drugs include etoposide, cyclophosphamide, fludarabine, treosulfan, busulfan, ATG, thiotepa.