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Clinical Trial
. 2024 Jan 23;8(2):416-428.
doi: 10.1182/bloodadvances.2023010591.

Low rate of nonrelapse mortality in under-4-year-olds with ALL given chemotherapeutic conditioning for HSCT: a phase 3 FORUM study

Peter Bader  1 , Ulrike Pötschger  2 , Jean-Hugues Dalle  3 , Laura M Moser  1 , Adriana Balduzzi  4 , Marc Ansari  5   6 , Jochen Buechner  7 , Tayfun Güngör  8 , Marianne Ifversen  9 , Gergely Krivan  10 , Herbert Pichler  11 , Marleen Renard  12 , Raquel Staciuk  13 , Petr Sedlacek  14 , Jerry Stein  15 , Jan Robert Heusel  1 , Tony Truong  16 , Jacek Wachowiak  17 , Akif Yesilipek  18 , Franco Locatelli  19 , Christina Peters  2   11
Affiliations
Clinical Trial

Low rate of nonrelapse mortality in under-4-year-olds with ALL given chemotherapeutic conditioning for HSCT: a phase 3 FORUM study

Peter Bader et al. Blood Adv. .

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is highly effective for treating pediatric high-risk or relapsed acute lymphoblastic leukemia (ALL). For young children, total body irradiation (TBI) is associated with severe late sequelae. In the FORUM study (NCT01949129), we assessed safety, event-free survival (EFS), and overall survival (OS) of 2 TBI-free conditioning regimens in children aged <4 years with ALL. Patients received fludarabine (Flu), thiotepa (Thio), and either busulfan (Bu) or treosulfan (Treo) before HSCT. From 2013 to 2021, 191 children received transplantation and were observed for ≥6 months (median follow-up: 3 years). The 3-year OS was 0.63 (95% confidence interval [95% CI], 0.52-0.72) and 0.76 (95% CI, 0.64-0.84) for Flu/Thio/Bu and Flu/Thio/Treo (P = .075), respectively. Three-year EFS was 0.52 (95% CI, 0.41-0.61) and 0.51 (95% CI, 0.39-0.62), respectively (P = .794). Cumulative incidence of nonrelapse mortality (NRM) and relapse at 3 years were 0.06 (95% CI, 0.02-0.12) vs 0.03 (95% CI: <0.01-0.09) (P = .406) and 0.42 (95% CI, 0.31-0.52) vs 0.45 (95% CI, 0.34-0.56) (P = .920), respectively. Grade >1 acute graft-versus-host disease (GVHD) occurred in 29% of patients receiving Flu/Thio/Bu and 17% of those receiving Flu/Thio/Treo (P = .049), whereas grade 3/4 occurred in 10% and 9%, respectively (P = .813). The 3-year incidence of chronic GVHD was 0.07 (95% CI, 0.03-0.13) vs 0.05 (95% CI, 0.02-0.11), respectively (P = .518). In conclusion, both chemotherapeutic conditioning regimens were well tolerated and NRM was low. However, relapse was the major cause of treatment failure. This trial was registered at www.clinicaltrials.gov as #NCT01949129.

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Conflict of interest statement

Conflict-of-interest disclosure: P.B. declares research grants from Neovii, Riemser, Medac, and Bristol Myers Squibb (to the institution); is a member of advisory boards for Novartis, Celgene, Amgen, Medac, and Servier (personal and institutional); has received speaker fees from Miltenyi, Jazz, Riemser, Novartis, and Amgen (to the institution); and declares a patent with and royalties from Medac. M.A. has received speaker and traveling fees from Jazz. J.B. has participated in advisory boards for Amgen, Novartis, Pfizer, and Janssen (to the institution), and has received speaker fees from Novartis. T.G. has received research grants from Jazz. M.I. has received honoraria for an advisory board role from Novartis. H.P. declares travel grants from Neovii. T.T. has received honoraria for consultancy and advisory board roles in Servier and Jazz. F.L. is a member of advisory boards for Amgen, Novartis, Bellicum Pharmaceuticals, Neovii, and Vertex, and has received speaker fees from Amgen, Novartis, Miltenyi, Medac, Jazz Pharmaceuticals, and Takeda, outside the submitted work. C.P. declares research grants from Amgen, Neovii, Riemser, Medac, and Jazz; is a member of advisory boards for Amgen, Neovii, Jazz, and Novartis; and has received speaker fees from Amgen, Neovii, Novartis, Medac, and Riemser. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
CONSORT diagram.
Figure 2.
Figure 2.
Key outcomes according to conditioning regimen. (A) Probability of OS; (B) probability of EFS over time; (C) CIR; (D) NRM; (E) probability of cGVHD; (F) probability of GRFS over time; and (G) probability of OS after relapse. Flu/Thio/Bu is shown in red and Flu/Thio/Treo in blue. n = 100 for Flu/Thio/Bu, and n = 91 for Flu/Thio/Treo for panels A to F; n = 41 for Flu/Thio/Bu, and n = 37 for Flu/Thio/Treo for panel G; 95% CIs are shown in parentheses. cGVHD, chronic GVHD.
Figure 3.
Figure 3.
Outcomes in comparison with those of historical cohorts of children aged ≥2 but <4 years with high-risk ALL undergoing HSCT. (A) Probability of OS over time and (B) probability of EFS over time, showing the ALL-SCT BFM International trial of TBI/Eto (blue; n = 16), the ALL-SCT BFM 2003 trial of TBI/Eto (red; n = 35), and children aged >2 but ≤4 years in the FORUM study of chemotherapeutic conditioning (green; n = 101).
See this image and copyright information in PMC

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