Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 14, Number 20, 2008


Contents

Advances in Hematopoietic Stem Cell Transplantation
Executive Editor: David A. Jacobsohn


Editorial: Pp. 1921-1922


Novel Preparative Regimens in Hematopoietic Stem Cell Transplantation Pp. 1923-1935
L. Lekakis, L. de Padua Silva and M. de Lima
[Abstract] [Purchase Article]


Therapeutic Drug Monitoring of Busulfan in Transplantation Pp. 1936-1949
J.A. Russell and S.B. Kangarloo
[Abstract] [Purchase Article]


The Use of Growth Factors in Hematopoietic Stem Cell Transplantation Pp. 1950-1961
I. Pusic and J.F. DiPersio
[Abstract] [Full Text Article]


Novel Drugs for the Prevention and Treatment of Acute GVHD Pp. 1962-1973
C. Cutler and J.H. Antin
[Abstract] [Purchase Article]


Chronic Graft-Versus-Host Disease Pp. 1974-1986
J. Bolaños-Meade and G.B. Vogelsang
[Abstract] [Purchase Article]


Non-Pharmacologic Strategies in Hematopoietic Stem Cell Transplantation Pp. 1987-1996
J. Schneiderman
[Abstract] [Purchase Article]


Viral Diagnostics and Antiviral Therapy in Hematopoietic Stem Cell Transplantation Pp. 1997-2010
E.J. Anderson
[Abstract] [Purchase Article]


Antifungal Agents in Hematopoietic Stem Cell Transplantation Pp. 2011-2021
G.I. Parameswaran, B.H. Segal and N.G. Almyroudis
[Abstract] [Purchase Article]




Abstracts


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Editorial: Advances in Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) has been established as a curative procedure for malignant diseases such as leukemia and non-malignant diseases such as severe combined immunodeficiency. Because HSCT carries significant risk of morbidity and mortality, it has up to now been reserved for patients with very high-risk diseases, where the chance of mortality is unacceptable without doing a transplant. The major barriers to successful HSCT are organ toxicity from the high-dose chemotherapy (and/or radiotherapy) preparative regimen, graft-versus-host disease, and infection.

Organ toxicity occurs early, generally a few weeks into transplant. Patients at higher risk are the older ones, and the more heavily pre-treated ones. An example of organ toxicity that occurs within the first three weeks of HSCT is veno-occlusive disease (VOD) of the liver. Patients have hyperbilirubinemia, ascites, weight gain, and tender hepatomegaly. When accompanied with additional organ toxicity, the survival after this complication is close to 10%. This complication is clearly associated with intensity of the preparative regimen and/or intensity of prior therapy. The last 10 years have witnessed a number of novel regimens that in general are very immunosuppressive but less myeloablative. The idea is to rely, for the eradication of malignancy, more on the graft-versus-tumor effect from the hematopoietic stem cells and less on the preparative chemotherapy. By doing this, one may have less upfront morbidity and mortality, and thus may be able to transplant older, sicker patients that were not candidates for transplant in the past. There have been successes already with certain diseases using novel regimens, and these are described in more detail by Lekakis et al. [1].

Given that busulfan is one of the key drugs used in transplant, Russell et al. [2] discuss its implications in therapeutic monitoring of this drug. Busulfan levels that are too high are associated with more organ toxicity whereas lower levels are associated with more relapse. Therefore, careful monitoring of this drug is essential now in the transplant setting.

In the last decade, a lot of the HSCT collections from related or unrelated donors have shifted from bone marrow harvest to peripheral blood stem cells (PBSC). PBSC collections can be done in the clinic and without sedation to the healthy donor. PBSC is also associated with faster engraftment for the recipient but also a higher risk of chronic graft-versus-host disease (GVHD). Because PBSC is such an important method of collection now, Pusic et al. [3] discuss the different agents, either available or under investigation, for mobilization of these cells prior to collection. These agents also may have a role post-transplant in shortening time to engraftment.

Once engraftment occurs, GVHD is a big concern. GVHD is essentially donor cells recognizing foreign tissues, generally skin, liver, and GI tract in the acute form. The risk of acute and chronic GVHD is higher in older patients and is higher with increasing degree of HLA mismatch. Chronic GVHD can last for many years and lead to significant disability and poor quality of life. Because GVHD can be associated with major morbidity as well as mortality, research is desperately needed in finding both therapies for prophylaxis and treatment of both acute and chronic GVHD. Cutler et al. [4] and Bolanos-Meade et al. [5] bring us up to date on the standard and investigational approaches in acute and chronic GVHD, respectively.

Many of these therapies for GVHD are associated with signification complications. Both organ toxicity (e.g. renal insufficiency) and major immunosuppression leading to infections are commonplace. Therefore, novel, less toxic, approaches are being looked at to treat and prevent GVHD. One of these is extracorporeal photopheresis (ECP), which relies on ex vivo treatment of lymphocytes with UV rays, leading to apoptosis and shifting the balance more towards immune tolerance rather than severe immunosuppression. Schneiderman et al. [6] brings us up to date on novel, non-pharmacologic, methods to treat and/or prevent GVHD which include ECP and mesenchymal stem cells (MSC).

Finally, infectious complications deserve major attention. The more intensive the therapy to prevent or treat GVHD, the higher the likelihood of infections we encounter. Because our therapies cause profound lymphopenia, fungal and viral are the most worrisome infections. The last few years have witnessed an incredible growth to the armamentarium of both monitoring and treating these infections. For example, it is now standard-of-care to follow CMV viral copies in the blood and treat pre-emptively, which has led almost to disappearance of CMV disease. Anderson et al. [7] discuss novel approaches with viruses and Almyroudis et al. [8] discuss novel approaches with fungi.

This is an exciting time for HSCT. We are now able to provide transplant to patients that a decade ago would not have been candidates. There is an increased use of alternative donor stem cells. HSCT can be performed in a safer way with fewer complications because of all the advances detailed in this issue.

References

[1] Lekakis L, de Padua Silva L, de Lima M. Novel Preparative Regimens in Hematopoietic Stem Cell Transplantation. Curr Pharm Des 2008; 14(20): 1923-1935.

[2] Russell JA, Kangarloo SB. Therapeutic Drug Monitoring of Busulfan in Transplantation. Curr Pharm Des 2008; 14(20): 1936-1949.

[3] Pusic I, DiPersio JF. The Use of Growth Factors in Hematopoietic Stem Cell Transplantation. Curr Pharm Des 2008; 14(20): 1950-1961.

[4] Cutler C, Antin JH. Novel Drugs for the Prevention and Treatment of Acute GVHD. Curr Pharm Des 2008; 14(20): 1962-1973.

[5] Bolaños-Meade J, Vogelsang GB. Chronic Graft-Versus-Host Disease. Curr Pharm Des 2008; 14(20): 1974-1986.

[6] Schneiderman J. Non-Pharmacologic Strategies in Hematopoietic Stem Cell Transplantation. Curr Pharm Des 2008; 14(20): 1987-1996.

[7] Anderson EJ. Viral Diagnostics and Antiviral Therapy in Hematopoietic Stem Cell Transplantation. Curr Pharm Des 2008; 14(20): 1997-2010.

[8] Parameswaran GI, Segal BH, Almyroudis NG. Antifungal Agents in Hematopoietic Stem Cell Transplantation. Curr Pharm Des 2008; 14(20): 2011-2021.


David A. Jacobsohn
Associate Professor of Pediatrics,
Northwestern University School of Medicine
Stem Cell Transplant Program
Children's Memorial Hospital
2300 Children’s Plaza, Box #30
Chicago, IL 60614
USA
Tel: 773-880-3694
Fax: 773-880-3742
E-mail: djacobsohn@childrensmemorial.org


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Novel Preparative Regimens in Hematopoietic Stem Cell Transplantation
L. Lekakis, L. de Padua Silva and M. de Lima

Hematopoietic stem cell transplantation is an established treatment modality for malignant and non-malignant diseases. Prior to the infusion of allogeneic or autologous cells, patients usually receive radiation or chemotherapy. This “preparative’ or ‘conditioning’ regimen provides treatment for the underlying disease and is expected to impair the recipient’s immune system and allow engraftment.

The last decade witnessed a significant reduction in treatment-related mortality, in great part a result of less toxic preparative regimens and improvements in supportive care. Another important trend has been the incorporation of newer drugs to ‘classic’ conditioning regimens, as illustrated by the addition of rituximab to BEAM and other combinations. It is expected that this trend will continue leading to increased cure rates by incorporation of targeted therapies to hematopoietic transplant. The next decade will likely witness further integration of new preparative regimens with graft engineering, and pharmacologic, cellular and immunologic post transplant interventions. The design of creative clinical trials that will allow the critical evaluation of the role of these new approaches in transplantation will also be a major challenge to the transplant community in the years to come.

In this article, we review newer transplant conditioning regimens and discuss their indications and future directions in this rapidly changing landscape.


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Therapeutic Drug Monitoring of Busulfan in Transplantation
J.A. Russell and S.B. Kangarloo

Busulfan is the only agent used in myeloablative regimens for hematopoietic stem cell transplantation for which therapeutic drug monitoring (TDM) has been widely used. Studies of oral busulfan (Bu) indicate wide intrapatient and interpatient variations in pharmacokinetic (PK) behavior, particularly in children. Dose adjustments of oral Bu based on TDM to bring exposures within established therapeutic ranges have been shown to reduce toxicity and improve outcomes. Intravenous (IV) Bu is becoming more widely used and has much more predictable PK. Outcomes with IV Bu appear to be superior to those achieved using oral Bu without TDM. However there is still at least a threefold variation in exposures achieved by the same dose of IV Bu in different individuals and a small proportion of patients will experience toxic exposures with current dosing regimens. Therapeutic monitoring with appropriate dose adjustment is therefore recommended for all patients treated with regimens containing high doses of Bu. Giving IV Bu at a fixed rate to adults will narrow the range of exposures but more work is needed to establish the best dosing regimen to bring as many exposures as possible within the target range. Studies of test dosing of IV Bu show that this strategy is more accurate when test and treatment doses are infused at the same rate. Finally, targeting exposures to the upper end of the therapeutic range may provide a safe approach to exploiting dose-intensity for the treatment of some malignancies.


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The Use of Growth Factors in Hematopoietic Stem Cell Transplantation
I. Pusic and J.F. DiPersio

Mobilized, peripheral blood stem cells (PBSC) are increasingly used for both autologous and allogeneic transplants. Granulocyte-colony-stimulating factor is the most widely used cytokine for mobilization. Several different mechanisms of stem cell mobilization have been proposed including protease-dependent and non-protease- dependent mechanisms. In autologous transplants, the addition of chemotherapy to mobilization can enhance the yield of PBSC collected but with substantial adverse effects, and not necessarily faster engraftment. In allogeneic transplants, the use of mobilized PBSC is associated with faster engraftment and donor chimerism compared to bone marrow. In the majority of studies, the rate of acute graft-versus-host disease (GVHD) has not been shown to be significantly higher with PBSC, but the rate of chronic GVHD appears to be increased. Several different strategies have been proposed for patients and donors who fail initial mobilization, including the use of novel agents. AMD3100 (Plerixafor) works by directly inhibiting the interaction between stromal cell-derived factor-1 and its receptor CXCR4, and mobilizes hematopoietic stem cells within hours. It is being studied alone or in conjunction with growth factors for PBSC mobilization in both autologous and allogeneic settings. Although the use of growth factors after PBSC transplantation results in faster neutrophil engraftment its impact on treatment-related mortality and survival does not appear significant. Here, we review the biology and methods of PBSC mobilization, the effect of growth factors on normal donors and the controversies of growth factor use in the post-transplant setting. We also review the data on novel agents for mobilization of stem cells.


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Novel Drugs for the Prevention and Treatment of Acute GVHD
C. Cutler and J.H. Antin

Acute graft-vs.-host disease (GVHD) remains one of the most significant barriers to successful allogeneic stem cell transplantation, accounting for a substantial portion of early transplant-related morbidity and mortality. Acute GVHD results from the complex interaction of donor T cells and host tissues that involves recognition of major and minor histocompatibility antigens in an inflammatory milieu. The current view of the pathogeneisis of acute GVHD is that it involves three steps: (1) tissue damage from conditioning regimen, (2) donor T-cell activation and (3) an inflammatory effector phase [1]. Recent studies demonstrating the importance of chemokines and regulatory T cells in acute GVHD have added further complexity to this model [2]. Within this context, clinical strategies that mitigate host tissue damage, down-regulate activated effector donor T cells, and reduce inflammatory cytokines in the early post transplant period should be effective in treating or preventing this condition. Indeed, strategies based, at least in part, on this model have continued to aid in the development of newer agents with promise in acute GVHD. However, until recently, it is only the cellular attack on host tissues that has been specifically targeted by GVHD prophylactic mechanisms, either with the use of a variety of pharmacologic agents or graft manipulation techniques, whereas therapeutics for the treatment of established acute GVHD have invoked the role of the cytokine cascades that may perpetuate ongoing GVHD reactions.

In this article, we will review the current standards for prevention and treatment of acute GVHD, and discuss novel drugs and therapeutics that hold promise for improved prevention and management of established acute GVHD.


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Chronic Graft-Versus-Host Disease
J. Bolaños-Meade and G.B. Vogelsang

Chronic graft-versus-host disease is the most common late, non-relapse complication of transplantation yet it is also one of the least studied. It is the primary cause of morbidity and mortality of long-term survivors of allogeneic bone marrow transplants. Like acute graft-versus-host disease, it does have a strong antitumor effect. The recent National Institutes of Health sponsored Chronic Graft-versus-Host Disease Consensus Conference has proposed new criteria for diagnosis and staging, pathology, biomarkers, response and supportive care. New understanding of the pathophysiology of chronic graft-versus-host disease (i.e. the role of B cells) is already having an impact on therapy. Novel agents such as pentostatin, mycophenolate mofetil, rituximab, extracorporeal photochemotherapy, etc. are improving the outcome of steroid refractory chronic graft-versus-host disease.


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Non-Pharmacologic Strategies in Hematopoietic Stem Cell Transplantation
J. Schneiderman

Allogeneic hematopoietic stem cell transplantation (HSCT) may be performed to treat a variety of malignant and non-malignant disorders by eradicating tumor, replacing a non-functioning with a normal immune system, or replenishing a deficient enzyme. While HSCT may provide cure for many patients, barriers such as acute and chronic graft-versus-host disease (a/cGVHD) and graft failure continue to challenge clinicians with considerable potential for morbidity and mortality. A thorough understanding of each disease process is essential to the development of both pharmacologic and non-pharmacologic therapies in this setting; unfortunately, acute and chronic GVHD, are distinct, complex entities, and medications used to prevent and treat them cause significant toxicities and leave patients at high risk for overwhelming infections. Standard pharmacologic therapies that are currently in use are limited in that they have the potential to cause significant toxicity without completely curing the disease. Novel, non-pharmacologic therapies for the prevention and treatment of acute and chronic GVHD must continue to be developed and studied in randomized trials. Given that the potential mechanisms of action of the non-pharmacologic therapies discussed herein attempt to modulate the cellular milieu that supports the development of GVHD, a brief discussion of GVHD and its pathophysiology is warranted; detailed discussions are provided by Cutler et al. and Bolanos-Meade elsewhere in the current issue. We will therefore focus on two non-pharmacological innovative forms of therapy, and potentially, prevention of GVHD.


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Viral Diagnostics and Antiviral Therapy in Hematopoietic Stem Cell Transplantation
E.J. Anderson

Viral infections are important causes of morbidity and mortality in hematopoietic stem cell transplant (HSCT) recipients. Some viruses, such as the respiratory and gastrointestinal viruses, are acquired from the healthcare or community in the midst of or after HSCT. Other viruses, such as the herpes-virus family, establish latency after resolution of primary infection but then may reactivate during the immunosuppression that occurs with HSCT. Due to the improved sensitivity and turn-around time with PCR-based molecular diagnostic methods, traditional viral diagnostic methods such as viral culture and rapid shell vial are rapidly being replaced or supplemented. Prophylactic and preemptive strategies are increasingly used to limit reactivation of viruses that have established latency. Improvements in diagnostics result in earlier viral detection and antiviral initiation which may improve outcomes. Newly identified viruses such as human metapneumovirus are being increasingly recognized as pathogens in HSCT recipients. Treatment strategies for viral pathogens continue to change as our understanding of these viral diseases improves.


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Antifungal Agents in Hematopoietic Stem Cell Transplantation
G.I. Parameswaran, B.H. Segal and N.G. Almyroudis

Invasive fungal infections are major complications of stem cell transplantation associated with significant morbidity and mortality. Allogeneic stem cell transplant recipients are at a significantly greater risk for fungal infection than recipients of autologous transplantation. Although with the wide use of fluconazole prophylaxis the incidence and associated mortality of invasive candidiasis has been minimized, mold diseases remain a significant complication during periods of prolonged immunosuppression for graft versus host disease. Posaconazole prophylaxis during periods of high risk was recently demonstrated to be effective in preventing fungal infections and associated mortality. Preemptive strategy employing laboratory markers and serial CT scans to identify mold infection at an early stage is promising. However its efficacy has to be validated in clinical trials. Several new antifungal agents have been introduced lately, characterized by improved safety profile and broader antifungal spectrum. Voriconazole has become the standard of care for the treatment of invasive aspergillosis. Finally there has been increasing interest on combination therapy for invasive aspergillosis due to the high rate of failure of the currently available antifungals, especially in the profoundly immunocompromised host.