A single‐center experience using alemtuzumab, fludarabine, melphalan, and thiotepa as conditioning for transplantation in pediatric patients with chronic granulomatous disease

Bhatt, Sima T.; Schulz, Ginny; Hente, Monica; Slater, Ashley; Murray, Lisa; Shenoy, Shalini; Bednarski, Jeffrey J.

doi:10.1002/pbc.28030

Cited by 9 publications

(5 citation statements)

References 17 publications

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“…23 A small prospective study in chronic granulomatous disease saw stable engraftment with no further interventions for mixed chimerism, with a preparatory regimen containing fludarabin, melphalan, alemtuzumab, and additional thiotepa. 24 We could not detect a significant effect of the stem cell source on mixed chimerism. It has been suggested that in primary immunodeficiency, PBSC may be preferable as stem cell source ensuring higher rates of donor chimerism.…”

Section: Discussionmentioning

confidence: 70%

Risk factors for mixed chimerism in children with hemophagocytic lymphohistiocytosis after reduced toxicity conditioning

Wustrau¹,

Greil

Sykora

et al. 2020

Pediatric Blood & Cancer

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Background Reduced toxicity conditioning for hematopoietic stem cell transplantation of patients with hemophagocyticlymphohistiocytosis (HLH) results in favorable survival, however at the expense of relevant rates of mixed chimerism. Factors predisposing to mixed chimerism remain to be determined. Procedure Patients with primary HLH transplanted 2009‐2016 after treosulfan‐ or melphalan‐based conditioning regimens were analyzed in a retrospective multicenter study for survival, engraftment, chimerism, and adverse events. Mixed chimerism was considered substantial if < 25% donor chimerism occurred and/or if secondary cell therapy was administered. Donor type, graft source, type of alkylating agent, type of serotherapy, and remission status were analyzed as potential risk factors in a multivariable logistic regression model. Results Among 60 patients, engraftment was achieved in 95%, and the five‐year estimated overall survival rate was 75%. Prevalence of any recipient chimerism was 48%. Substantial recipient chimerism was recorded in 32% of patients. Secondary post‐HSCT cell therapy was administered in 30% of patients. A human leukocyte antigen (HLA)‐mismatched donor (< 10/10) was the only significant risk factor for the occurrence of substantial recipient chimerism (P = 0.01; odds ratio, 5.8; CI 95%, 1.5‐26.3). Conclusion The use of an HLA‐matched donor is the most important factor to avoid substantial recipient chimerism following treosulfan ‐or melphalan‐based conditioning in primary HLH.

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Section: Discussionmentioning

confidence: 70%

Risk factors for mixed chimerism in children with hemophagocytic lymphohistiocytosis after reduced toxicity conditioning

Wustrau¹,

Greil

Sykora

et al. 2020

Pediatric Blood & Cancer

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“…Both protocols are based on the very effective fludarabine/ melphalan backbone, for which very low relapse incidence rates in myeloid malignancies are reported [54]. Notably, conditioning with fludarabine, thiotepa, and melphalan have been previously reported by other groups [28][29][30]. Interestingly, no statistically significant differences were observed on adjusted overall survival rates between FBMand FTM-treated patients, despite higher HCT-CI score, more previous chemotherapy treatments and impaired lung function in FTM-treated patients.…”

Section: Discussionmentioning

confidence: 93%

“…However, FTM-treated patients suffered more frequently mild to moderate mucositis. Thiotepa has been associated with mucositis in several studies prior auto-HCT [58] and allo-HCT [12,[28][29][30]. Eder et al [12] reported a frequency of 46.8% in 323 ALL patients receiving thiotepa as conditioning.…”

Section: Discussionmentioning

confidence: 99%

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Comparison of reduced-toxicity conditioning protocols using fludarabine, melphalan combined with thiotepa or carmustine in allogeneic hematopoietic cell transplantation

Duque‐Afonso

Ihorst

Waterhouse

et al. 2020

Bone Marrow Transplant

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The age of patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) has increased during the last decades, mainly due to improved reduced-intensity/toxicity conditioning protocols. A reduced-intensity conditioning based on fludarabin, carmustin/BCNU and melphalan (FBM) has been previously developed at our institution. Since we observed detrimental effects in individual patients with compromised lung function, efforts have been made in order to replace BCNU by thiotepa (FTM) to reduce toxicity. In this study, we retrospectively analyzed the outcome, GvHD incidence, lung function and organ toxicity of patients with a median age of 62 years (range 21-79) transplanted for malignant disease (96.7%, 62.3% in intermediate/advanced disease stage) at our institution after conditioning with FBM (n = 136) or FTM (n = 105) between 2013 and 2017. Median follow-up was 868 days (range 0-2615). In multivariate analysis for overall survival, no difference was detected between both conditioning protocols in the presence of impaired lung function, age, lower performance, and liver disease previous allo-HCT. In the subgroup analysis, FTM was not inferior to FBM in patients with pulmonary disease prior allo-HCT, lymphoid malignancies, and higher comorbidity index. In conclusion, the reduced-intensity FBM and FTM conditioning protocols show adequate antineoplastic efficacy and are suitable for patients with impaired lung function.

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“…Therefore, when given in normal dosages at the same day relative to graft infusion, alemtuzumab may yield in more potent suppression of GvHD and GF, but potentially also leads to poor T-cell recovery. Still, alemtuzumab is currently used for the indication of hyperinflammation, with subcutaneous low dosing implemented to overcome slow or absent T-cell recovery (Bhatt et al, 2020). TDM of alemtuzumab is mainly focused on preventing underdosing (Arnold et al, 2021).…”

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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A single‐center experience using alemtuzumab, fludarabine, melphalan, and thiotepa as conditioning for transplantation in pediatric patients with chronic granulomatous disease

Cited by 9 publications

References 17 publications

Risk factors for mixed chimerism in children with hemophagocytic lymphohistiocytosis after reduced toxicity conditioning

Risk factors for mixed chimerism in children with hemophagocytic lymphohistiocytosis after reduced toxicity conditioning

Comparison of reduced-toxicity conditioning protocols using fludarabine, melphalan combined with thiotepa or carmustine in allogeneic hematopoietic cell transplantation

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

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