Pharmacokinetics and clinical activity of very low-dose alemtuzumab in transplantation for acute leukemia

Spyridonidis, Alexandros; Liga, Maria; Triantafyllou, Evangelia; Themeli, Maria; Marangos, Markos; Καρακάντζα, Μαρίνα; Zoumbos, Nicholas

doi:10.1038/bmt.2010.308

Cited by 18 publications

(19 citation statements)

References 17 publications

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“…Chakraverty et al showed that the dose of alemtuzumab can be safely reduced to a total of 30 mg in reduced-intensity HSCT from an HLA-identical sibling donor [29]. A Greek group evaluated the efficacy of alemtuzumab at a total dose of 10-20 mg on days -2 and -1 before HSCT [30]. Even with alemtuzumab at these very low doses, there was no Grade II-IV acute GVHD after HSCT from a sibling donor.…”

Section: Discussionmentioning

confidence: 99%

In vivo T‐cell depletion with alemtuzumab in allogeneic hematopoietic stem cell transplantation: Combined results of two studies on aplastic anemia and HLA‐mismatched haploidentical transplantation

et al. 2013

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We evaluated the efficacy of in vivo T-cell depletion with alemtuzumab in two prospective studies according to the International Conference on Harmonisation (ICH)-Good Clinical Practice (ICH-GCP) guidelines; one was for patients with aplastic anemia (AA study) and the other was for patients who were undergoing hematopoietic stem cell transplantation (HSCT) from a 2-or 3-antigen-mismatched haploidentical donor (MM study). The final dose of alemtuzumab in these studies was 0.16 mg/kg/day for 6 days. At this dose, all of the 12 and 11 patients in the AA and MM studies, respectively, achieved initial engraftment and the incidences of Grade II-IV acute graft-versus-host disease (GVHD) were 0% and 18%. While cytomegalovirus (CMV) frequently reactivated, none of the patients developed fatal CMV disease. Transplantation-related mortality within 1 year after HSCT was observed in only two and one patients, respectively. The numbers of CD41 and CD81 T-cells and T-cell receptor rearrangement excision circles remained low within 1 year after HSCT. These findings suggest that the use of alemtuzumab at this dose in a conditioning regimen enables safe allogeneic HSCT even from a 2-or 3-antigen-mismatched donor. However, the use of a lower dose of alemtuzumab should be explored in future studies to accelerate immune recovery after HSCT. Am. J. Hematol. 88:294-300, 2013. V C 2013 Wiley Periodicals, Inc. IntroductionGraft-versus-host disease (GVHD) is an important complication after allogeneic hematopoietic stem cell transplantation (HSCT), especially in the presence of an HLA-mismatch between the donor and recipient. Alemtuzumab is a humanized monoclonal antibody against CD52, and the use of alemtuzumab in the conditioning regimen before HSCT has been shown to decrease the incidences of acute and chronic GVHD through the in vivo depletion of donor T cells [1]. A growing body of evidence supports the efficacy of alemtuzumab at preventing acute GVHD in a variety of HSCT settings [2][3][4][5][6][7][8][9]. In addition, we and others have reported that alemtuzumab enables HLA-mismatched haploidentical HSCT without the ex vivo depletion of donor T cells [10,11]. We administered alemtuzumab at 0.2 mg/kg/day for 6 days before allogeneic HSCT from a 2-or 3-anitigen-mismatched related donor in 12 patients [10]. All patients achieved neutrophil engraftment and the cumulative incidence of Grade III to IV acute GVHD was only 9%. Rizzieri et al. used alemtuzumab at a total dose of 100 mg spread over 5 days in reduced-intensity haploidentical HSCT without ex vivo T-cell depletion [11]. The incidences of Grade III-IV acute GVHD and transplant-related mortality were 8% and 10.2%, respectively. Therefore, in vivo T-cell depletion using alemtuzumab enables haploidentical HSCT without excessive GVHD.With regard to allogeneic HSCT for aplastic anemia (AA), alemtuzumab has been incorporated into the conditioning regimen to achieve sustained engraftment with minimal toxicity and GVHD [12]. The incidence of graft failure was 9.5% for HSCT from an HLA-ma...

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Section: Discussionmentioning

confidence: 99%

In vivo T‐cell depletion with alemtuzumab in allogeneic hematopoietic stem cell transplantation: Combined results of two studies on aplastic anemia and HLA‐mismatched haploidentical transplantation

et al. 2013

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“…These data were confirmed by Spyridonidis et al . in a small study of 18 patients who received 10 mg alemtuzumab before sibling and matched unrelated SCT [40]. Chakraverty et al also demonstrated that dose reduction of alemtuzumab to 30 mg given on day -1 effectively prevents GvHD and is associated with more rapid lymphocyte recovery after HLA-identical sibling SCT [41].…”

Section: Pharmacology and Dosing Of Alemtuzumab In Transplant Protmentioning

confidence: 99%

Alemtuzumab in allogeneic hematopoetic stem cell transplantation

Poiré

Besien

2011

Expert Opinion on Biological Therapy

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Introduction With the use of reduced-intensity conditioning (RIC), early toxicity of allogeneic stem cell transplantation (SCT) has been much reduced. Graft-versus-host disease (GvHD) causes morbidities and mortality. Alemtuzumab is a mAb directed against CD52. When administered prior to transplant it leads to T-cell depletion. Incorporation of alemtuzumab in RIC results in low rates of GvHD and treatment-related mortality (TRM) in haematological diseases, even in the setting of mismatched-donor transplantation. Areas covered The use of alemtuzumab for GvHD in SCT. The benefit of alemtuzumab-based conditioning is partially offset by increased disease relapse due to impaired graft-versus-tumor effect (GvT) and by slower immune reconstitution, necessitating special precautions. While GvHD is prevented with alemtuzumab, post-SCT interventions are often required. Most studies find that alemtuzumab-based conditioning results in decreased chronic GvHD and TRM, but also in decreased progression-free survival. Overall survival after 3 – 5 years is usually equivalent and quality of life may be improved because of a lower incidence of sequelae of chronic GvHD. Many aspects of alemtuzumab treatment are under investigation. Expert opinion Alemtuzumab reduces GvHD and TRM after SCT. Use of alemtuzumab requires awareness and strict management of the risk of opportunistic infections and of an increased risk of disease recurrence.

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“…61, 62 Alemtuzumab is lymphotoxic at concentrations > 100 ng/ml. 63 When antigen concentration is high, half-life is short because the monoclonal antibody binds to its epitope and rapidly cleared. As the antigen is depleted, clearance decreases and half-life increases.…”

Section: Pharmacokinetics/dynamics Of the Conditioning Regimenmentioning

confidence: 99%

Optimizing drug therapy in pediatric SCT: Focus on pharmacokinetics

Jacobson

Wiseman

Militano

2014

Bone Marrow Transplant

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Given age-related differences in drug metabolism and indications for hematopoietic stem cell transplantation (HSCT), personalized drug dosing of the conditioning regimen and post-transplant immunosuppression may reduce graft rejection, relapse rates, and toxicity in pediatric HSCT recipients. This manuscript summarizes the pharmacokinetic/dynamic data of HSCT conditioning and postgrafting immunosuppression, presented at the First Annual Pediatric Bone Marrow Transplant Consortium meeting in April 2013. Personalized dosing of BU to a target plasma exposure reduces graft rejection in children and improves relapse/toxicity rates in adults. Current weight-based dosing achieves the target BU exposure in only a minority (24.3%) of children. The initial BU dose should be based on the European Medicines Agency nomogram or population pharmacokinetic models to improve the numbers of children achieving the target exposure. There are limited pharmacokinetic data for treosulfan, cyclophosphamide, fludarabine, and alemtuzumab as HSCT conditioning in children. For postgrafting immunosuppression, mycophenolic acid (MPA) clearance may be increased in younger children (< 12 years). The preferred MPA pharmacokinetic monitoring parameters and target range are still evolving in HSCT recipients. Multi-institutional trials incorporating properly powered pharmacokinetic/dynamic studies are needed to assess the effect of variability in the plasma exposure of drugs/metabolites on clinical outcomes in pediatric HSCT recipients.

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Pharmacokinetics and clinical activity of very low-dose alemtuzumab in transplantation for acute leukemia

Cited by 18 publications

References 17 publications

In vivo T‐cell depletion with alemtuzumab in allogeneic hematopoietic stem cell transplantation: Combined results of two studies on aplastic anemia and HLA‐mismatched haploidentical transplantation

In vivo T‐cell depletion with alemtuzumab in allogeneic hematopoietic stem cell transplantation: Combined results of two studies on aplastic anemia and HLA‐mismatched haploidentical transplantation

Alemtuzumab in allogeneic hematopoetic stem cell transplantation

Optimizing drug therapy in pediatric SCT: Focus on pharmacokinetics

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