Experience with a Reduced Toxicity Allogeneic Transplant Regimen for Non-CGD Primary Immune Deficiencies Requiring Myeloablation

Chandra, Sharat; Chandrakasan, Shanmuganathan; Saldaña, Blachy J. Dávila; Bleesing, Jack J.; Jordan, Michael B.; Kumar, Ashish; Grimley, Michael; Krupski, Christa; Davies, Stella M.; Khandelwal, Pooja; Marsh, Rebecca

doi:10.1007/s10875-020-00888-2

Cited by 17 publications

(20 citation statements)

References 23 publications

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“…infusion of busulfan between 3.2 and 4.8 mg/kg over 3 h, with dose calculated based on patient total weight as per Australian Busulfex® product information 23 except for two obese patients where an adjusted dosing weight (adjusted body weight 25) was used 23 . Subsequent doses across 4 days of treatment were modified to target an AUC cum that was individualized for each patient based on clinical and disease factors 13,24–26 . Blood samples for busulfan plasma concentration measurement were collected following each dose, from an alternative lumen to that used for administration, at 0 h (predose), 3 h (immediately following first flush), and 3.25, 4, 5, 6, and 8 h after the start of the infusion.…”

Section: Methodsmentioning

confidence: 99%

Population pharmacokinetic model for once‐daily intravenous busulfan in pediatric subjects describing time‐associated clearance

Lawson

Staatz

Fraser

et al. 2022

CPT Pharmacom & Syst Pharma

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This study aimed to characterize the population pharmacokinetics (PK) of busulfan focusing on how busulfan clearance (CL) changes over time during once‐daily administration and assess different methods for measuring busulfan exposure and the ability to achieve target cumulative exposure under different dosing adjustment scenarios in pediatric stem cell transplantation recipients. Daily serial blood sampling was performed and concentration‐time data were analyzed using a nonlinear mixed‐effects approach. The developed PK model was used to assess achievement of target exposure under six dose‐adjustment scenarios based on simulations performed in RStudio (RxODE package)®. A total of 2491 busulfan plasma concentration–time measurements were collected from 95 patients characterizing 379 dosing days. A two‐compartment model with time‐associated CL best described the data with a typical CL of 14.5 L/h for an adult male with 62 kg normal fat mass (NFM; equivalent to 70 kg total body weight), typical volume of distribution central compartment (V1) of 40.6 L/59 kg NFM (equivalent to 70 kg total body weight), and typical volume of distribution peripheral compartment of 3.57 L/62 kg NFM. Model interindividual variability in CL and V1 was 14.7% and 34.9%, respectively, and interoccasional variability in CL was 6.6%. Patient size described by NFM, a maturation component, and time since start of treatment significantly influenced CL. Simulations demonstrated that using model‐based exposure estimates with each dose, and either a proportional dose‐adjustment calculation or model‐based calculated individual CL estimates to support dose adjustments, increased proportion of subjects attaining cumulative exposure within 5% of target compared with using noncompartmental analysis (100% vs. 0%). A time‐associated reduction in CL during once‐daily busulfan treatment was described.

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Section: Methodsmentioning

confidence: 99%

Population pharmacokinetic model for once‐daily intravenous busulfan in pediatric subjects describing time‐associated clearance

Lawson

Staatz

Fraser

et al. 2022

CPT Pharmacom & Syst Pharma

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“…The need for serotherapy in patients with hyperinflammation in the context of HCT for immune deficiencies is quite clear. Currently, rabbit ATG (Thymoglobulin, Grafalon) and alemtuzumab, an anti-CD52 monoclonal antibody, are available for this indication (Fox et al, 2018;Slatter et al, 2018;Chandra et al, 2021). Alemtuzumab is more potent, as reflected in a lower lympholytic level (Lane et al, 2014;Marsh et al, 2016), with a longer half-life compared to ATG (Admiraal et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Drug Monitoring of Anti-Thymocyte Globulin in Allogeneic Stem Cell Transplantation: Proof of Concept

et al. 2022

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Anti-thymocyte globulin (ATG), a polyclonal antibody, is used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-vs.-host-disease (GvHD) and graft failure (GF). Overexposure to ATG leads to poor early T-cell recovery, which is associated with viral infections and poor survival. Patients with severe inflammation are at high risk for GF and GvHD, and may have active infections warranting swift T-cell recovery. As ATG exposure may be critical in these patients, individualized dosing combined with therapeutic drug monitoring (TDM) may improve outcomes. We describe the individualized dosing approach, an optimal sampling scheme, the assay to measure the active fraction of ATG, and the workflow to perform TDM. Using a previously published population pharmacokinetic (PK) model, we determine the dose to reach optimal exposures associated with low GvHD and rejection, and at the same time promote T-cell recovery. Based on an optimal sampling scheme, peak and trough samples are taken during the first 3 days of once-daily dosing. The fraction of ATG able to bind to T-cells (active ATG) is analyzed using a bio-assay in which Jurkat cells are co-cultured with patient’s plasma and the binding is quantified using flow cytometry. TDM is performed based on these ATG concentrations on the third day of dosing; subsequent doses can be adjusted based on the expected area under the curve. We show that individualized ATG dosing with TDM is feasible. This approach is unique in the setting of antibody treatment and may result in better immune reconstitution post-HCT and subsequently better survival chances.

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“…36 In the study of Chandra et al, using a reduced busulfan-based conditioning regimen, toxicity was low, so the results were comparable to treosulfan-based regimens. 37 There are four patients diagnosed with WAS in our study. MRD transplantation was performed in one patient, and haploidentical transplantation was performed in the other three.…”

Section: Discussionmentioning

confidence: 85%

“…32 When immunode ciency studies with busulfan were examined, it was reported that one-year OS was around 90% in reduced-dose busulfan use. 33 In studies with classical dose busulfan, these rates are about 53 to 77%. 34,35 Since using Treosulfan, the most common early-stage toxicity has been skin toxicity.…”

Section: Discussionmentioning

confidence: 99%

The Impact of Treosulfan -based Conditioning for Inborn Errors of Immunity: Is Dose Monitoring Crucial?

Ersoy

Çipe

Fışgın

et al. 2023

Preprint

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In children with inborn errors of immunity (IEI) who receive a hematopoietic stem cell transplant (HSCT), treosulfan-based conditioning is currently preferred. This study aimed to investigate early and late outcomes and examine the effect of treosulfan dose monitoring on outcomes. Seventy-three pediatric patients receiving this management between 2015 and 2022 were included. Overall survival rate was 80%, and event-free survival was 67.8%. A larger treosulfan dose AUC increased the rate of early toxicity (p=0.034) and slowed lymphocyte engraftment (r=0.290; p=0.030). Underlying disease, treosulfan AUC, donor type, stem cell type, number of immunosuppressive agents, the dose of anti-thymocyte globulin, and post-transplantation cyclophosphamide did not increase acute graft-versus-host disease. The risk of mixed chimerism (MC) in patients with autoimmune lymphoproliferative syndrome and leukocyte adhesion deficiency was higher than those with severe combined immunodeficiency (p=0.021 and p=0.014, respectively). The risk of MC was lower in those receiving peripheral blood stem cells (SC) compared with bone marrow-derived SC (OR=0.204, p=0.022). The AUC of treosulfan dose was not associated with poorer late outcomes. Treosulfan is an agent that can be used safely in the IEI patient group; level measurement appears essential to identify early toxicities. Prospective studies with more extended follow-up periods are needed.

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Experience with a Reduced Toxicity Allogeneic Transplant Regimen for Non-CGD Primary Immune Deficiencies Requiring Myeloablation

Cited by 17 publications

References 23 publications

Population pharmacokinetic model for once‐daily intravenous busulfan in pediatric subjects describing time‐associated clearance

Population pharmacokinetic model for once‐daily intravenous busulfan in pediatric subjects describing time‐associated clearance

Therapeutic Drug Monitoring of Anti-Thymocyte Globulin in Allogeneic Stem Cell Transplantation: Proof of Concept

The Impact of Treosulfan -based Conditioning for Inborn Errors of Immunity: Is Dose Monitoring Crucial?

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