Hematopoietic cell transplant in pediatric acute myeloid leukemia after similar upfront therapy; a comparison of conditioning regimens

Versluys, A. B.; Boelens, Jaap Jan; Pronk, Cornelis Jan; Lankester, Arjan C.; Bordon, Victoria; Buechner, Jochen; Ifversen, Marianne; Jackmann, Natalja; Sundin, Mikael; Vettenranta, Kim; Abrahamsson, Jonas; Mellgren, Karin

doi:10.1038/s41409-020-01201-w

Cited by 12 publications

(11 citation statements)

References 22 publications

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“…A retrospective analysis in paediatric AML using a common backbone of induction chemotherapy followed by three different chemotherapy conditioning regimens suggested that Clofarabine-Fludarabine-Busulfan had good anti-leukaemic activity with low NRM. In comparison, Busulfan-Cyclophosphamide was associated with higher relapse incidence, while Busulfan-Cyclophosphamide-Melphalan was associated with higher incidence of acute GVHD (166).…”

Section: Use Of Clofarabine In Hsct Conditioningmentioning

confidence: 83%

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

et al. 2021

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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.

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Section: Use Of Clofarabine In Hsct Conditioningmentioning

confidence: 83%

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

et al. 2021

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“…The addition of clofarabine (Clo) to the conditioning regimen with Bu and Flu prior to HSCT in pediatric hematological malignancies has proven to be a safe and promising strategy ( Alatrash et al, 2016 ; Versluys et al, 2021 ). Similar as fludarabine, clofarabine is a purine analogue and a prodrug that is converted intracellularly to its active metabolite clofarabine-5’-triphosphate.…”

Section: Chemotherapymentioning

confidence: 99%

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

et al. 2022

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Allogeneic hematopoietic stem cell transplantation (HSCT) is an established curative treatment that has significantly improved clinical outcome of pediatric patients with malignant and non-malignant disorders. This is partly because of the use of safer and more effective combinations of chemo- and serotherapy prior to HSCT. Still, complications due to the toxicity of these conditioning regimens remains a major cause of transplant-related mortality (TRM). One of the most difficult challenges to further improve HSCT outcome is reducing toxicity while maintaining efficacy. The use of personalized dosing of the various components of the conditioning regimen by means of therapeutic drug monitoring (TDM) has been the topic of interest in the last decade. TDM could play an important role, especially in children who tend to show greater pharmacokinetic variability. However, TDM should only be performed when it has clear added value to improve clinical outcome or reduce toxicity. In this review, we provide an overview of the available evidence for the relationship between pharmacokinetic parameters and clinical outcome or toxicities of the most commonly used conditioning agents in pediatric HSCT.

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“…In a retrospective comparison with other busulfan-based conditioning regimens for HCT in pediatric AML, CloFluBu resulted in better leukemia-free survival compared with busulfan-cyclophosphamide (BuCy), and lower aGvHD risk compared with BuCy and BuCyMel conditioning regimens. 12 Our findings indicate that CloFluBu is a successful conditioning regimen for high-risk pediatric AML patients, with respectable survival chances, limited relapse risk, and low risks of aGvHD, VOD, and graft failure.…”

Section: Discussionmentioning

confidence: 58%

“…In a retrospective analysis comparing CloFluBu with other conditioning regimens (BuCy and BuCyMel) in pediatric HCT for AML, CloFluBu showed comparable disease control to BuCyMel, but with less acute graft-versus-host disease (aGvHD). 12 Targeted drug monitoring (TDM) of busulfan was an important factor in preventing toxicity, such as aGvHD. So far, no reports exist on the efficacy and toxicity of CloFluBu conditioning prior to HCT in pediatric ALL.…”

Section: Introductionmentioning

confidence: 99%

Clofarabine-fludarabine-busulfan in HCT for pediatric leukemia: an effective, low toxicity, TBI-free conditioning regimen

et al. 2022

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We prospectively studied CloFluBu-conditioning in allogeneic Hematopoietic Cell Therapy (HCT) for lymphoid- and myeloid malignancies, and hypothesized that CloFluBu provides a less toxic alternative to conventional conditioning regimens, with adequate anti-leukemic activity. All patients receiving their first HCT, from 2011-2019, were included and received CloFluBu. Primary endpoint was Event Free Survival (EFS). Secondary endpoints were Overall Survival (OS), Graft-versus-Host-Disease (GvHD)-Relapse-Free Survival (GRFS), Treatment Related Mortality (TRM), Cumulative Incidence of Relapse (CIR), acute and chronic GvHD, and veno-occlusive disease (VOD). Cox Proportional Hazard- and Fine and Gray competing-risk models were used for data analysis. 155 Children were included; 60 acute lymphoid leukemia (ALL), 69 acute myeloid leukemia (AML), and 26 other malignancies (mostly MDS-EB). Median age was 9.7 (0.5-18.6) years. Estimated 2-yr EFS was 72.0% ± 6.0 in ALL, and 62.4% ± 6.0 in AML patients. TRM in the whole cohort was 11.0% ± 2.6, incidence of aGvHD III-IV at 6 months was 12.3% ± 2.7, extensive chronic GvHD at 2-yr was 6.4% ± 2.1. Minimal residual disease-positivity prior to HCT was associated with higher CIR, both in ALL and AML. CloFluBu showed limited toxicity and encouraging EFS. CloFluBu is a potentially less toxic alternative to conventional conditioning regimens. Randomized prospective studies are needed.

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Hematopoietic cell transplant in pediatric acute myeloid leukemia after similar upfront therapy; a comparison of conditioning regimens

Cited by 12 publications

References 22 publications

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

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

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

Clofarabine-fludarabine-busulfan in HCT for pediatric leukemia: an effective, low toxicity, TBI-free conditioning regimen

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