Total Body Irradiation Forever? Optimising Chemotherapeutic Options for Irradiation-Free Conditioning for Paediatric Acute Lymphoblastic Leukaemia

Abstract

Total-body irradiation (TBI) based conditioning prior to allogeneic hematopoietic stem cell transplantation (HSCT) is generally regarded as the gold-standard for children >4 years of age with acute lymphoblastic leukaemia (ALL). Retrospective studies in the 1990's suggested better survival with irradiation, confirmed in a small randomised, prospective study in the early 2000's. Most recently, this was reconfirmed by the early results of the large, randomised, international, phase III FORUM study published in 2020. But we know survivors will suffer a multitude of long-term sequelae after TBI, including second malignancies, neurocognitive, endocrine and cardiometabolic effects. The drive to avoid TBI directs us to continue optimising irradiation-free, myeloablative conditioning. In chemotherapy-based conditioning, the dominant myeloablative effect is provided by the alkylating agents, most commonly busulfan or treosulfan. Busulfan with cyclophosphamide is a long-established alternative to TBI-based conditioning in ALL patients. Substituting fludarabine for cyclophosphamide reduces toxicity, but may not be as effective, prompting the addition of a third agent, such as thiotepa, melphalan, and now clofarabine. For busulfan, it's wide pharmacokinetic (PK) variability and narrow therapeutic window is well-known, with widespread use of therapeutic drug monitoring (TDM) to individualise dosing and control the cumulative busulfan exposure. The development of first-dose selection algorithms has helped achieve early, accurate busulfan levels within the targeted therapeutic window. In the future, predictive genetic variants, associated with differing busulfan exposures and toxicities, could be employed to further tailor individualised busulfan-based conditioning for ALL patients. Treosulfan-based conditioning leads to comparable outcomes to busulfan-based conditioning in paediatric ALL, without the need for TDM to date. Future PK evaluation and modelling may optimise therapy and improve outcome. More recently, the addition of clofarabine to busulfan/fludarabine has shown encouraging results when compared to TBI-based regimens. The combination shows activity in ALL as well as AML and deserves further evaluation. Like busulfan, optimization of chemotherapy conditioning may be enhanced by understanding not just the PK of clofarabine, fludarabine, treosulfan and other agents, but also the pharmacodynamics and pharmacogenetics, ideally in the context of a single disease such as ALL.

Evaluation of PreTBI (Total Body Irradiation) and PosTBI Fatigue Severity Scale Scores in the ALL (Acute Lymphocytic Leukemia) Patients Preparing for Stem Cell Transplant

“…Long term effects including secondary malignancies, cardiac or metabolic effects guided researchers to use myeloablative regimens such as busulfan or treosulfan. Encouraging but not 100 % similar results were shown after this study [1]. Pulmonary, ocular, cardiac, neurological or renal toxicities may be seen after TBI but these are manageable.…”

Therapeutic Drug Monitoring of Conditioning Agents in Pediatric Allogeneic Stem Cell Transplantation; Where do We Stand?

“…For busulfan, only the studies that report either a hazard ratio (HR), odds ratio (OR) or relative risk (RR) were selected to limit results and keep the review concise. For a detailed overview of busulfan PK studies we refer to two recent reviews ( Ben Hassine et al, 2021 ; Lawson et al, 2021 ). Studies were described in chronological order.…”

GWAS identifies genetic clusters of cardiometabolic risk factors in continental Africans

“…LINC02273 is also associated with reduced monocyte count (a proposed predictive risk biomarker for asymptomatic CVD development and brotic disease), smoking initiation, and acute myeloid leukemia (the development in cases with metabolic disease is thought to be a by-product of the total body irradiation therapy 18,19 ).…”