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Acute Lymphoblastic Leukaemia in the Youngest: Haematopoietic Stem Cell Transplantation and Beyond.

ABSTRACT: The ALL SCTped 2012 FORUM (For Omitting Radiation Under Majority age) trial compared outcomes for children ≥4 years of age transplanted for acute lymphoblastic leukaemia (ALL) who were randomised to myeloablation with a total body irradiation (TBI)-based or chemotherapy-based conditioning regimen. The TBI-based preparation was associated with a lower rate of relapse compared with chemoconditioning. Nevertheless, the age considered suitable for TBI was progressively raised over time to spare the most fragile youngest patients from irradiation-related complications. The best approach to use for children <4 years of age remains unclear. Children diagnosed with ALL in their first year of life, defined as infants, have a remarkably poorer prognosis compared with older children. This is largely explained by the biology of their ALL, with infants often carrying a KMT2A gene rearrangement, as well as by their fragility. In contrast, the clinical presentations and biological features of ALL in children >1 year but <4 years often resemble those presented by older children. In this review, we explore the state of the art regarding haematopoietic stem cell transplantation (HSCT) in children <4 years, the preparative regimens available, and new developments in the field that may influence treatment decisions.

SUBMITTER: Balduzzi A

PROVIDER: S-EPMC8911028 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Acute Lymphoblastic Leukaemia in the Youngest: Haematopoietic Stem Cell Transplantation and Beyond.

Balduzzi Adriana A Buechner Jochen J Ifversen Marianne M Dalle Jean-Hugues JH Colita Anca M AM Bierings Marc M

Frontiers in pediatrics 20220224

The ALL SCTped 2012 FORUM (For Omitting Radiation Under Majority age) trial compared outcomes for children ≥4 years of age transplanted for acute lymphoblastic leukaemia (ALL) who were randomised to myeloablation with a total body irradiation (TBI)-based or chemotherapy-based conditioning regimen. The TBI-based preparation was associated with a lower rate of relapse compared with chemoconditioning. Nevertheless, the age considered suitable for TBI was progressively raised over time to spare the ...[more]

PMID: 35281233

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Project description:BackgroundThe role of conditioning intensity and stem cell source on modifying pre-transplantation risk in allogeneic haematopoietic stem cell transplantation (HSCT) is a matter of debate, but crucial when benchmarking centres.MethodsThis Retrospective, multicenter exploratory-validation analysis of 9103 patients, (55.5% male, median age 50 years; 1-75 years range) with an allogeneic HSCT between 2010 and 2016 from a matched sibling (N = 8641; 95%) or matched unrelated donor (N = 462; 5%) for acute myeloid (N = 6432; 71%) or acute lymphoblastic (N = 2671; 29%) leukaemia in first complete remission, and reported by 240 centres in 30 countries to the benchmark database of the European Society for Blood and Marrow Transplantation (EBMT) searched for factors associated with use of transplant techniques (standard N = 6375;70% or reduced intensity conditioning N = 2728;30%, respectively bone marrow N = 1945;21% or peripheral blood N = 7158;79% as stem cell source), and their impact on outcome.FindingsTreatment groups differed significantly from baseline population (p < 0.001), and within groups regarding patient-, disease-, donor-, and centre-related pre-transplantation risk factors (p < 0.001); choice of technique did depend on pre-transplantation risk factors and centre (p < 0.001). Probability of overall survival at 5 years decreased systematically and significantly with increasing pre-transplantation risk score (score 2 vs 0/1 HR: 1·2, 95% c.i. [1·1-1·.3], p = 0.002; score 3 vs 0/1 HR: 1·5, 95% c.i. [1·3-1·7], p < 0.001; score 4/5/6 vs 0/1 HR: 1·9, 95% c.i. [1·6-2·2], p < 0.001) with no significant differences between treatment groups (likelihood ratio test on interaction: p = 0.40). Overall survival was significantly associated with selection steps and completeness of information (p < 0.001).InterpretationPatients' pre-transplantation risk factors determine survival, independent of transplant techniques. Transplant techniques should be regarded as centre policy, not stratification factor in benchmarking. Selection criteria and completeness of data bias outcome. Outcomes may be improved more effectively through better identifying pre-transplantation factors as opposed to refinement of transplant techniques.FundingThe study was funded by EBMT.

Project description:Total body irradiation (TBI) has been a pivotal component of the conditioning regimen for allogeneic myeloablative haematopoietic stem cell transplantation (HSCT) in very-high-risk acute lymphoblastic leukaemia (ALL) for decades, especially in children and young adults. The myeloablative conditioning regimen has two aims: (1) to eradicate leukaemic cells, and (2) to prevent rejection of the graft through suppression of the recipient's immune system. Radiotherapy has the advantage of achieving an adequate dose effect in sanctuary sites and in areas with poor blood supply. However, radiotherapy is subject to radiobiological trade-offs between ALL cell destruction, immune and haematopoietic stem cell survival, and various adverse effects in normal tissue. To diminish toxicity, a shift from single-fraction to fractionated TBI has taken place. However, HSCT and TBI are still associated with multiple late sequelae, leaving room for improvement. This review discusses the past developments of TBI and considerations for dose, fractionation and dose-rate, as well as issues regarding TBI setup performance, limitations and possibilities for improvement. TBI is typically delivered using conventional irradiation techniques and centres have locally developed heterogeneous treatment methods and ways to achieve reduced doses in several organs. There are, however, limitations in options to shield organs at risk without compromising the anti-leukaemic and immunosuppressive effects of conventional TBI. Technological improvements in radiotherapy planning and delivery with highly conformal TBI or total marrow irradiation (TMI), and total marrow and lymphoid irradiation (TMLI) have opened the way to investigate the potential reduction of radiotherapy-related toxicities without jeopardising efficacy. The demonstration of the superiority of TBI compared with chemotherapy-only conditioning regimens for event-free and overall survival in the randomised For Omitting Radiation Under Majority age (FORUM) trial in children with high-risk ALL makes exploration of the optimal use of TBI delivery mandatory. Standardisation and comprehensive reporting of conventional TBI techniques as well as cooperation between radiotherapy centres may help to increase the ratio between treatment outcomes and toxicity, and future studies must determine potential added benefit of innovative conformal techniques to ultimately improve quality of life for paediatric ALL patients receiving TBI-conditioned HSCT.

Project description:Minimal residual disease (MRD) assessment plays a central role in risk stratification and treatment guidance in paediatric patients with acute lymphoblastic leukaemia (ALL). As such, MRD prior to haematopoietic stem cell transplantation (HSCT) is a major factor that is independently correlated with outcome. High burden of MRD is negatively correlated with post-transplant survival, as both the risk of leukaemia recurrence and non-relapse mortality increase with greater levels of MRD. Despite growing evidence supporting these findings, controversies still exist. In particular, it is still not clear whether multiparameter flow cytometry and real-time quantitative polymerase chain reaction, which is used to recognise immunoglobulin and T-cell receptor gene rearrangements, can be employed interchangeably. Moreover, the higher sensitivity in MRD quantification offered by next-generation sequencing techniques may further refine the ability to stratify transplant-associated risks. While MRD quantification from bone marrow prior to HSCT remains the state of the art, heavily pre-treated patients may benefit from additional staging, such as using 18F-fluorodeoxyglucose positron emission tomography/computed tomography to detect focal residues of disease. Additionally, the timing of MRD detection (i.e., immediately before administration of the conditioning regimen or weeks before) is a matter of debate. Pre-transplant MRD negativity has previously been associated with superior outcomes; however, in the recent For Omitting Radiation Under Majority age (FORUM) study, pre-HSCT MRD positivity was associated with neither relapse risk nor survival. In this review, we discuss the level of MRD that may require pre-transplant therapy intensification, risking time delay and complications (as well as losing the window for HSCT if disease progression occurs), as opposed to an adapted post-transplant strategy to achieve long-term remission. Indeed, MRD monitoring may be a valuable tool to guide individualised treatment decisions, including tapering of immunosuppression, cellular therapies (such as donor lymphocyte infusions) or additional immunotherapy (such as bispecific T-cell engagers or chimeric antigen receptor T-cell therapy).

Dataset Information

Acute Lymphoblastic Leukaemia in the Youngest: Haematopoietic Stem Cell Transplantation and Beyond.

Publications

Acute Lymphoblastic Leukaemia in the Youngest: Haematopoietic Stem Cell Transplantation and Beyond.

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