Overview of Hematopoietic Cell Transplantation Immunology

Martin, Paul J.; Shlomchik, Warren D.

doi:10.1002/9781118416426.ch9

Cited by 2 publications

(10 citation statements)

References 159 publications

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“…3 Postgraft immunosuppression varies between myeloablative and RIC regimens (Table 2). Since myeloablative conditioning has been available for longer, there are more data from patients receiving myeloablative alloHCT than from those receiving RIC alloHCT.…”

Section: Understanding Allohct To Conduct Pharmacokinetic/pharmacomentioning

confidence: 99%

“…Graft rejection after alloHCT can manifest as either a lack of initial engraftment or development of pancytopenia and marrow aplasia after initial engraftment. 3 Rejection, drug toxicity, sepsis, and certain viral infections can all cause graft failure. 3 An absence of donor cells and the presence of recipient T-cells are key findings to support the diagnosis of rejection in a patient with graft failure.…”

Section: Pharmacodynamic Endpointsmentioning

confidence: 99%

“…3 Rejection, drug toxicity, sepsis, and certain viral infections can all cause graft failure. 3 An absence of donor cells and the presence of recipient T-cells are key findings to support the diagnosis of rejection in a patient with graft failure. 3 Because of the durable persistence of donor cells, however, rejection is unlikely, even when recipient T-cells can be detected.…”

Section: Pharmacodynamic Endpointsmentioning

confidence: 99%

“…To achieve this cure, a delicate balance must be maintained between the immune system of the host and the donor stem cells (graft) that were infused into the host. 1 The transplantation of donor cells that are not genetically identical (i.e., allogeneic) can result in bi-directional immunologic reactions. 2 This contrasts with solid organ transplantation, where the graft generally has a limited number of cells with immunologic function and the main concern is preventing rejection of the donor organ by the recipient’s immune system.…”

Section: Introductionmentioning

confidence: 99%

“…2 This contrasts with solid organ transplantation, where the graft generally has a limited number of cells with immunologic function and the main concern is preventing rejection of the donor organ by the recipient’s immune system. 3 In alloHCT, grafting of cells from one individual to another provokes immunologic reactions involved in engraftment of the donor cells, graft-versus-host disease (GVHD), control of a malignancy (termed graft versus tumor, GVT), the development of tolerance, and immune reconstitution. 2 These immunologic reactions are influenced by the conditioning regimen (also termed preparative regimen), the type and source of the donor graft, and the postgraft immunosuppressive regimen (Figure 1), all of which are essential components of the alloHCT procedure.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Pharmacokinetics, Pharmacodynamics and Pharmacogenomics of Immunosuppressants in Allogeneic Haematopoietic Cell Transplantation: Part I

2015

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Although immunosuppressive treatments and target concentration intervention (TCI) have significantly contributed to the success of allogeneic hematopoietic cell transplant (alloHCT), there is currently no consensus on the best immunosuppressive strategies. Compared to solid organ transplant, alloHCT is unique because of the potential for bi-directional reactions (i.e., host-versus-graft and graft-versus-host). Postgraft immunosuppression typically includes a calcineurin inhibitor (cyclosporine or tacrolimus) and a short course of methotrexate after high-dose myeloablative conditioning or a calcineurin inhibitor and mycophenolate mofetil after reduced-intensity conditioning. There are evolving roles for the antithymyocyte globulins (ATG) and sirolimus as postgraft immunosuppression. A review of the pharmacokinetics and TCI of the main postgraft immunosuppressants is presented in this two-part review. All immunosuppressants are characterized by large intra- and interindividual pharmacokinetic variability and by narrow therapeutic indices. It is essential to understand immunosuppressants’ pharmacokinetic properties and how to use them for individualized treatment incorporating TCI to improve outcomes. TCI, which is mandatory for the calcineurin inhibitors and sirolimus, has become an integral part of postgraft immunosuppression. TCI is usually based on trough concentration monitoring, but other approaches include measurement of the area under the concentration-time curve (AUC) over the dosing interval or limited sampling schedules with maximum a posteriori Bayesian personalization approaches. Interpretation of pharmacodynamic results is hindered by the prevalence of studies enrolling only a small number of patients, variability in the allogeneic graft source, and variability in postgraft immunosuppression. Given the curative potential of alloHCT, the pharmacodynamics of these immunosuppressives deserves to be explored in depth. The development of sophisticated systems pharmacology models and improved TCI tools are needed to accurately evaluate patients’ exposure to drugs in general and to immunosuppressants in particular. Sequential studies, first without and then with TCI, should be conducted to validate the clinical benefit of TCI in homogenous populations; randomized trials are not feasible due to higher priority research questions in alloHCT. In part I of this article, we review the alloHCT process to facilitate optimal design of pharmacokinetic and pharmacodynamics studies. We also review the pharmacokinetics and TCI of calcineurin inhibitors and methotrexate.

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Section: Understanding Allohct To Conduct Pharmacokinetic/pharmacomentioning

confidence: 99%

Section: Pharmacodynamic Endpointsmentioning

confidence: 99%

Section: Pharmacodynamic Endpointsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Pharmacokinetics, Pharmacodynamics and Pharmacogenomics of Immunosuppressants in Allogeneic Haematopoietic Cell Transplantation: Part I

2015

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Pretransplant C‐reactive Protein as A Prognostic Marker in Allogeneic Stem Cell Transplantation

et al. 2014

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We evaluated the prognostic role of baseline levels of C-reactive protein (CRP) as well as CRP levels during conditioning in patients undergoing myeloablative allogeneic stem cell transplantation (SCT). Furthermore, we studied the impact of baseline clinical factors and conditioning regimens on CRP levels in the same period. We conducted a population-based retrospective study of 349 patients undergoing SCT at the National Danish SCT centre between January 2000 and January 2009. CRP levels increased significantly during the conditioning and peaked at day À3 before infusion of the graft. Elevated CRP was associated with older age, non-malignant disease, reduced pretransplant Karnofsky score and high-risk leukaemia. By univariate and multivariate analyses, increased CRP levels (>10 mg/l) before the start of treatment (day À7) and at the day of graft infusion (day 0) were associated with decreased overall survival [HR 1.35 (95% CL) (1.18-1.54); P < 0.0001] and increased treatment-related mortality [1.5 (1.24-1.82); P < 0.0001]. Similar findings were seen for mean CRP levels during the conditioning. CRP was not associated with risk of relapse or aGvHD in multivariate analysis. This study suggests that increased CRP levels before and during the conditioning are associated with baseline clinical factors and that elevated pretransplant CRP levels predict a poorer survival in SCT.

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Overview of Hematopoietic Cell Transplantation Immunology

Cited by 2 publications

References 159 publications

Pharmacokinetics, Pharmacodynamics and Pharmacogenomics of Immunosuppressants in Allogeneic Haematopoietic Cell Transplantation: Part I

Pharmacokinetics, Pharmacodynamics and Pharmacogenomics of Immunosuppressants in Allogeneic Haematopoietic Cell Transplantation: Part I

Pretransplant C‐reactive Protein as A Prognostic Marker in Allogeneic Stem Cell Transplantation

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