Y Böttiger

Bio: Y Böttiger is an academic researcher from Karolinska University Hospital. The author has contributed to research in topics: Transplantation. The author has an hindex of 1, co-authored 1 publications receiving 23 citations.

Cyclosporine A (CsA) 2-h concentrations vary between patients without correlation to graft-versus-host disease after allogeneic haematopoietic stem cell transplantation

Abstract: Cyclosporine A (CsA) therapy based on 2-h concentrations (C2) after oral administration has demonstrated low acute rejection rates after solid organ transplantation We analysed the correlation between C2 and trough (C0) levels of oral CsA therapy in samples obtained twice in consecutive weeks from 58 patients during their first admission for allogeneic haematopoietic stem cell transplantation Also 8-h concentration curves were obtained from 23 patients The mean (range) CsA dose was 332 (167–763) and 255 (113–575) mg/day for patients with matched unrelated donor (MUD) and human leukocyte antigen identical sibling donor (Sib), respectively Median (range) C0 and C2 were 254 (145–332) and 898 (419–1466) ng/ml in MUD patients, and 130 (93–265) and 554 (196–988) ng/ml in Sib patients In MUD patients with either aGVHD grade

Stem cell transplantation

Abstract: New sources of hematopoietic stem cells (HSCs) are now being explored world-wide, scientific societies have changed their names, and both the latest authoritative multiauthor texts, Barrett and Treleaven published in 1998 and this one published in 1999, have abandoned the classical emphasis on bone marrow as the source of stem cells in order to take account of other potential sources. In this book there is no doubt that the chapters by Metcalf on human hematopoiesis and Lansdorp on stem self-renewal are both stimulating and rewarding. It is a pity that they had no chance to give their views on the unexpected hematopoietic potential demonstrated by adult neural stem cells reported recently in the columns of Sciencewhich has amazed many of us! It is obviously impossible to review critically even a small proportion of the chapters in this magnificent volume. Suffice it to say that each of the original chapters have been substantially updated, and there is now a wealth of entirely new contributions which will interest biologists and clinicians. I was particularly fascinated by the chapters on tolerance (Sykes–Strober) and mixed chimerism (Storb–Yu– McSweeney), the latter outlining the rationale for the exciting new concept of non-myeloablative stem cell allotransplantation. However, as one of the proponents of intensive immunosuppression for severe autoimmune diseases, followed by allogeneic or autologous HSCs, I personally doubt whether achieving mixed chimerism will prevent resensitization to autoantigens and so ensure ‘cure’, as proposed in this section. Other outstandingly exciting chapters are on cord blood usage (Broxmeyer–Smith) and i utero transplantation (Flake–Zanjani). All the clinical sections, both on allogeneic and autologous HSC transplants, are upto-date and with no exceptions excellent, and all of them make good reading both for experts and tyros. It is indeed encouraging to learn that even advanced AL amyloidosis, a hitherto devastating disease, may consistently respond to high-dose melphalan followed by autologous HSC support (Comenzo). Entire new sections have been devoted to autologous HSC transplantation in solid tumors, such as breast, smallcell lung, germ cell, ovarian, brain, neuroblastoma and other solid tumors. Non-malignant diseases are discussed in depth, with an especially fascinating chapter on Fanconi anemia (Wagner–Davies–Auerbach). Transplantation of organs or cells must be seen as a ‘bridge’ that should permit the clinician to control potentially fatal diseases in the hope that more reliable biologically based treatments will eventually be developed. In the final chapter Ernest Beutler, after having taught us about ‘Polystems’ and the drugs TetraP (glorified SCF) and Thromboproliferin (but it is already here!), predicts that in the 21st or 22nd century transplantation will be required no more. Sure. But in the meantime this book will help contemporary HSC transplanters to widen their knowledge and, hopefully, to improve their clinical results.

Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II.

Abstract: Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of the calcineurin inhibitors and methotrexate. In this article (Part II), we review the pharmacokinetics, pharmacodynamics, and pharmacogenomics of mycophenolic acid (MPA), sirolimus, and the antithymocyte globulins (ATG). We then discuss target concentration intervention (TCI) of these postgraft immunosuppressants in alloHCT patients, with a focus on current evidence for TCI and on how TCI may improve clinical management in these patients. Currently, TCI using trough concentrations is conducted for sirolimus in alloHCT patients. Several studies demonstrate that MPA plasma exposure is associated with clinical outcomes, with an increasing number of alloHCT patients needing TCI of MPA. Compared with MPA, there are fewer pharmacokinetic/dynamic studies of rabbit ATG and horse ATG in alloHCT patients. Future pharmacokinetic/dynamic research of postgraft immunosuppressants should include '-omics'-based tools: pharmacogenomics may be used to gain an improved understanding of the covariates influencing pharmacokinetics as well as proteomics and metabolomics as novel methods to elucidate pharmacodynamic responses.

Assessment of the Cylex ImmuKnow cell function assay in pediatric heart transplant patients.

Abstract: Background The Cylex ImmuKnow (Cylex, Columbia, MD) cell function assay (CICFA) is a commercially available test of immune response that purportedly identifies solid organ transplant patients at risk for either acute rejection (AR) or infection. Data on the utility of this test in pediatric heart transplant patients are very limited. This study tested the hypothesis that CICFA is a clinically useful test in this transplant population. Methods All children undergoing heart transplantation at the study center (1989–2006) for whom CICFA levels were obtained were reviewed. The association of CICFA levels with episodes of AR and significant infections was determined. Results Among 83 patients (34 girls, 41%), 367 CICFA levels were obtained (median, 4.0; interquartile range [IQR], 2.0–6.0 per patient). There were 26 episodes of AR in 17 patients (20%) and 38 infections in 34 patients (41%). CICFA levels were similar among patients with AR at the time of the CICFA measurement (median, 325 [IQR, 163–480] adenosine triphosphate [ATP] ng/ml) vs patients without AR (median, 330 [IQR, 227–441] ATP ng/ml; p = 0.36). CICFA levels were similar among patients with infections within 1 month of CICFA measurement (median, 295 [IQR, 216–366] ATP ng/ml) and those without infections (median, 330 [IQR, 226–453] ATP ng/ml; p = 0.24). Conclusions The CICFA is not predictive of AR or significant infections in pediatric heart transplant patients. On the basis of the available evidence, this assay cannot be recommended as part of the routine management of pediatric heart transplant patients.

The use of pharmacokinetic models in paediatric onco-haematology: effects on clinical outcome through the examples of busulfan and cyclosporine.

Abstract: Overall survival after allogeneic haematopoietic stem cell transplantation (HSCT) is reduced by the high rate of transplantation-related mortality (TRM), especially because of liver veno-occlusive disease (VOD) or acute graft-vs.-host disease (GVHD) because of the toxicity or inefficacy of busulfan and cyclosporine (CsA), respectively. Results of clinical outcome of previous studies performed to optimize busulfan and CsA therapy by controlling their pharmacokinetic variability by means of maximum a posteriori (MAP) Bayesian individualization of both drugs are presented. The 90-day VOD-free survival was significantly higher in patients with individualized busulfan doses: 97% vs. 76%. Monitoring CsA trough blood concentrations allowed us to obtain a successful GVHD outcome (mild or moderate GVHD and graft vs. leukaemia effect (GVL) in malignant diseases and no GVHD (in non-malignant ones) in the majority of our patients. Severe GVHD occurred in <5% of patients. TRM in children can be significantly decreased by using population pharmacokinetic models and MAP Bayesian individualization of dose regimens for drugs such as CsA and busulfan.

CsA exposure is associated with acute GVHD and relapse in children after SCT

Abstract: CsA is commonly used after haematological SCT (HSCT) as GVHD prophylaxis. In solid organ transplantation, area under the blood concentration vs time curve (AUC) correlates with clinical outcome. However, in HSCT, it has not been determined whether the AUC is superior to trough level monitoring to optimize clinical efficacy of CsA therapy. Therefore, the aim of this study was to investigate the relationships between CsA trough levels and/or AUC early after HSCT with clinical outcome. A total of 91 children (1.1-17.3 years) were treated consecutively with HSCT for a haematological malignancy. CsA trough levels were obtained and were used to estimate the AUC, retrospectively, with a NONMEM (Non-Linear Mixed Effects Modelling) method. Subsequently, these exposure parameters were correlated to the occurrence of acute GVHD, relapse risk (RR) and OS. Low CsA trough levels were found to correlate with the occurrence of acute GVHD. In addition, a CsA AUC over 3000 mcg h/l in AML patients was associated with a higher RR and a reduced OS. This was not the case for ALL patients. Thus, monitoring CsA exposure early after HSCT and adjusting the CsA dose to a predefined target trough level and AUC may provide a tool to influence GVHD/GVL balance.