Role Of Stem Cell Transplantation Research Articles

Clinical and scientific advances in the Philadelphia-chromosome negative chronic myeloproliferative disorders.

The chronic myeloproliferative disorders are clonal hematopoietic stem cell disorders and include chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and agnogenic myeloid metaplasia (AMM). These diseases are characterized by clonal expansion of the myeloid compartment, increased marrow angiogenesis, and varying risks for blastic transformation. A clear molecular abnormality exists (t(9;22) leading to the fusion of BCR-Abl) only for CML, which led to effective targeted therapy (STI-571). Since no similar pathogenetic mechanism has been discovered for the t(9;22) negative chronic myeloproliferative disorders, their respective diagnosis is currently based on a variety of rather cumbersome diagnostic criteria. Polycythemia vera is distinguished from reactive erythrocytosis through erythropoietin independent growth of erythroid progenitors in vitro, suppressed levels of endogenous erythropoietin, possible overexpression of PRV-1 (polycythemia rubra vera-1), decreased c-Mpl expression on megakaryocytes, as well as overexpression of bcl-xL, and potentially aberrant activity of the Jak-Stat pathway. ET is defined by thrombocytosis and is distinguished from reactive states by decreased megakaryocyte c-Mpl expression, and a propensity for thrombosis. AMM has been associated with a variety of observations including increased concentrations of pro-fibrotic cytokines, increased angiogenesis, and myeloid expansion. AMM is often indistinguishable clinically and prognostically from the advanced phases of other CMPD (specifically post-polycythemic and post-thrombocythemia myeloid metaplasia), all of which are subentities of a diagnosis of myelofibrosis with myeloid metaplasia (MMM). The management of CMPD patients is quite varied given the broad range of disease severity and survival observed. The role of stem cell transplantation is limited by the age and comorbidities encountered in CMPD patients. Since no broadly applicable therapy effects the mortality of the CMPD, management currently focuses on the prevention/palliation of disease morbidity (i.e. vascular complications, pruritus, organomegaly, constitutional symptoms). Palliative strategies which currently focus on non-specific myelosuppresion, will hopefully be soon replaced by targeted therapies as insight into pathogenetic mechanisms of these diseases evolves.

Acute myeloid leukemia.

In this chapter, Drs. Keating and Willman review recent advances in our understanding of the pathophysiology of acute myeloid leukemia (AML) and allied conditions, including the advanced myelodysplastic syndromes (MDS), while Drs. Goldstone, Avivi, Giles, and Kantarjian focus on therapeutic data with an emphasis on current patient care and future research studies. In Section I, Dr. Armand Keating reviews the role of the hematopoietic microenvironment in the initiation and progression of leukemia. He also discusses recent data on the stromal, or nonhematopoietic, marrow mesenchymal cell population and its possible role in AML. In Section II, Drs. Anthony Goldstone and Irit Avivi review the current role of stem cell transplantation as therapy for AML and MDS. They focus on data generated on recent Medical Research Council studies and promising investigation approaches. In Section III, Dr. Cheryl Willman reviews the current role of molecular genetics and gene expression analysis as tools to assist in AML disease classification systems, modeling of gene expression profiles associated with response or resistance to various interventions, and identifying novel therapeutic targets. In Section IV, Drs. Hagop Kantarjian and Francis Giles review some promising agents and strategies under investigation in the therapy of AML and MDS with an emphasis on novel delivery systems for cytotoxic therapy and on targeted biologic agents.

Stem cell transplantation for mantle cell lymphoma: should it ever be used outside clinical trials?

The outlook for patients with mantle cell lymphoma is poor. The reported median survival in most published series is only 3 to 4 years, and even the most favorable prognostic groups have median survival rates of only 5 years, with no evidence of cure. The use of autologous and allogeneic stem cell transplantation in this disease has increased dramatically in recent years. Despite encouraging reports from single centers and registries, the impact of stem cell transplantation on the outcome for mantle cell lymphoma is unclear. Optimal first-line regimens for mantle cell lymphoma have yet to be defined, and it is therefore difficult to place the role of first remission transplantation in an appropriate context. Prospective randomized trials have been difficult to design and conduct in the absence of a well-defined 'standard' treatment. The role of stem cell transplantation as a salvage strategy is also unknown, although available data suggest that it does not improve survival in heavily pre-treated patients. In the absence of clear evidence for a survival advantage for patients receiving stem cell transplants for mantle cell lymphoma, entry into clinical trials should be a priority.

Allogeneic and autologous transplantation for chronic lymphocytic leukemia.

Autologous and allogeneic transplantation are increasingly used in the management of patients with chronic lymphocytic leukemia. Many questions regarding patient selection, efficacy and outcome are unresolved, hence a review of the literature through Medline search. Autologous transplantation for CLL has been used mainly in selected patients under the age of 60. Conditioning typically involves total body irradiation (TBI). Bone marrow and more recently peripheral blood stem cells are used. Treatment-related mortality in most series is less than 10%. Molecular remissions after autologous transplantation are common, and clinical remissions can be prolonged in some patients. Randomized studies are needed to establish whether autologous transplantation confers a survival benefit over standard chemotherapy approaches. Allogeneic transplantation has a considerable treatment-related mortality, but durable remissions sometimes occur in patients with advanced disease. The use of non-myeloablative 'mini-transplants' has been investigated as a method to reduce treatment-related mortality, but prolonged follow-up will be required to establish the cure rate obtained with this procedure. Autologous and allogeneic transplantation are promising treatment modalities. Further refinements of transplant techniques and properly designed prospective studies are necessary to establish the role of stem cell transplantation in the overall management of CLL.

Cord Blood Characteristics (Role in Stem Cell Transplantation)

Cord Blood Characteristics (Role in Stem Cell Transplantation)

Therapy for childhood acute myeloid leukemia: Role of allogeneic bone marrow transplantation

Acute myeloid leukemia (AML) has one of the lowest survival rates of childhood cancers. The first significant improvement in AML therapy started with the introduction of the now standard regimen of 3 days of anthracyclines and 7 days of cytarabine (Ara-C), the so-called 3+7 combinations. Several different therapeutic approaches have been taken in attempts to improve the outcome, including intensification of therapy both for remission induction and in the postremission phase. Intensification of postremission therapy included multiple courses of high-dose chemotherapy and/or myeloablative therapy followed by stem- cell rescue from either allogeneic or autologous sources. Furthermore, risk-tailored therapy is now possible, by cytogenetic risk stratification, promptness of remission induction, and identification of distinct clinical subgroups such as children with Down syndrome. This approach is rapidly changing potential therapeutic strategies for children with AML. It is in this changing mileu that we address the proper role of stem-cell transplantation, a modality that is changing (like chemotherapy) with expanding stem-cell sources and approaches to decrease transplant-related toxicity.

Stem cell transplantation for indolent lymphoma.

Stem cell transplantation (SCT) has become the treatment of choice for patients with relapsed aggressive non-Hodgkin's lymphoma (NHL). The role of SCT in the management of patients with low-grade NHL remains more controversial, although increasing numbers of patients with advanced-stage follicular lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia are now undergoing SCT. To date, most patients with NHL have been treated with autologous SCT, currently using peripheral blood stem cells (PBSC) mobilized by chemotherapy and recombinant growth factors. There is increasing concern regarding toxicity of autologous SCT, especially the higher than expected long-term risk of development of myelodysplastic syndrome. This, among other factors, has led to renewed interest in the role of allogeneic SCT for patients with NHL. A major advantage of allogeneic SCT is the potential to exploit a graft-versus-lymphoma effect, and many studies are underway exploring the possibility of manipulating donor cells to maximize T cell responsiveness against lymphoma.