Effect of clofarabine and fludarabine exposure on outcome after pediatric allogeneic hematopoietic cell transplantation

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Allogeneic hematopoietic cell transplantation (allo-HCT) is used as consolidation therapy in children with high-risk hematological malignancies.This curative treatment option comes with high morbidity and mortality.One of the critical challenges in improving clinical outcome is designing an effective conditioning regimen with limited toxicity.The core of standard conditioning regimens for allo-HCT in children consists of total body irradiation (TBI) or alkylating cytotoxic agents.Conventionally, the nucleoside analog fludarabine (Flu) has been included in most reduced-intensity regimens together with the alkylating agent IV busulfan (Bu).The second-generation purine analog clofarabine (Clo) was recently added to the conditioning 1 due to its synergistic antileukemic effect in combination with FluBu.2,3 A recently published multicenter prospective study in pediatric patients with acute lymphoblastic leukemia (ALL) showed that TBI-based conditioning results in better outcome than chemotherapy-based conditioning.4 Nevertheless, these findings should be weighed against the well-known late toxic effects of TBI. 5 We recently reported that CloFluBu is a good alternative for TBI-based conditioning in ALL in first complete remission and an effective, less toxic strategy in patients with acute myeloid leukemia (AML).6 Optimizing the pharmacokinetic (PK) exposures of conditioning agents can improve clinical outcomes, and the need for an optimal exposure has so far been reported for Bu, 7,8 Flu, 9,10 and antithymocyte globulin (ATG).11,12 PK studies on Clo in children undergoing allo-HCT show that dosing based on body weight and renal function would lead to the best predictable exposure.13,14 Studies associating Clo PK with clinical outcome after allo-HCT have not been performed so far.Furthermore, the reduced Flu dose in the CloFluBu conditioning compared with the dose in the FluBu conditioning leads to the question whether the previously reported risk for therapy-related mortality (TRM), associated with CD4 immune reconstitution (IR), and graft failure also applies in the context of CloFluBu conditioning.9,10 Therefore, we conducted a retrospective cohort analysis to examine the effect of Flu and Clo exposures on clinical outcome after allo-HCT.All patients with high-risk hematological malignancies receiving an allo-HCT in the University Medical Center Utrecht/Princess M áxima Center between October 2011 and October 2019 were included after written informed consent in accordance with the Declaration of Helsinki.The study was approved under trial number 11/063-k.Patients were treated as previously described.6 Conditioning consisted of Clo and Flu on 4 consecutive days at a daily dosage of 30 mg/m 2 and 10 mg/m 2 , respectively, in combination with IV-administered Bu, targeted at an area under the concentration time curve (AUC T0-∞ ) of 85 to 95 mg*hour/L.7,8 ATG was administered, and subsequent total exposures were determined as previously reported.6,11,12,15,16 Absolute numbers of immune cells were measured by flow cytometry at least every other week up to 12 weeks after allo-HCT and monthly thereafter.

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