Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019045 (hemoglobinopathies)
 2,704 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hematologic malignancy has rarely been reported in adults with sickle cell disease. We describe four sickle cell patients (two with hemoglobin SC, two with hemoglobin SS) who developed hematologic malignancy (acute myeloblastic leukemia, multiple myeloma, malignant histiocytosis, and Hodgkin's disease). Three of the cases represent the first adult association between SC or SS hemoglobinopathy and the particular malignancy involved. Sickle hemoglobin does not appear to exert a protective effect against childhood hematologic malignancies, suggesting that better survival in sickle cell disease may be accompanied by an increased incidence of hematologic neoplasms in adulthood. Karyotypic analysis revealed alterations of chromosome 5 in two sickle cell patients with leukemia, raising the possibility of a chromosomal link between the two diseases. Further epidemiologic and cytogenetic studies are needed to define the relationship between hematologic malignancy and sickle cell disease.
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PMID:Hematologic malignancy in sickle cell disease: report of four cases and review of the literature. 345 91

We have analyzed the factors associated with engraftment in 216 recipients of T-cell depleted allogeneic HLA identical sibling marrow transplants using Campath 1 monoclonal antihuman lymphocyte (CD52) antibodies. The patient population consisted of 168 patients with hematologic malignancies, 26 with severe aplastic anemia (SAA), and 22 with hemoglobinopathies, half of whom received marrow treated in vitro with Campath-1M (IgM) and half received marrow with Campath-1G (IgG2b isotype). Patients with durable engraftment had fast hematopoietic recovery: SAA patients reached ANC > 0.5 x 10(6)/L on Day 14; those with leukemia attained ANC > 0.5 x 10(6)/L on Days 18, 17, and 15 for ANLL, ALL and CML respectively, while patients with thalasemia reached ANC > 0.5 x 10(6)/L on Day 21. Overall, 24 patients (17 with leukemia, 4 with SAA, and 3 with thalassemia) suffered graft failure: 10 patients (all grafted with Campath-1M) rejected their grafts, while 14 others (9 grafted with Campath-1M, and 5 with 1G isotype) never engrafted (p = 0.009). Multivariate analysis revealed that neither pretransplant protocol, nor stage of disease or type of antibody used, donor sex and ABO match had any impact on engraftment. The variables favorably associated with engraftment were older age (p = 0.030, RR = 1.016) and CFU-GM number (p = 0.013, RR = 1.001). Patients with ANLL or SAA had a better chance to engraft (p = 0.027, RR = 1.400; and p = 0.003, RR = 2.677, respectively) compared to patients with thalassemia (p = 0.001, RR = 0.551). A higher concentration of Campath-1 antibody in vitro and in vivo adversely affected engraftment. Our data show that satisfactory engraftment can be achieved in patients transplanted with Campath-1 treated marrow allografts. However, despite the measures undertaken to prevent rejection, graft failure still poses a problem. Further pretransplant immunosuppression and perhaps more selective T-cell depletion may reduce the increased graft failure in these patients.
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PMID:Engraftment of marrow allografts treated with Campath-1 monoclonal antibodies. 1039 Jan 97

Advances in molecular biology of the last 30 tears have transformed the field of hematology. Molecular analysis has clarified the pathogenesis of a host of hematologic disorders, including hemoglobinopathies, coagulation disorders, hypercoaguable states, and hematologic malignancies. This volume is aimed at bringing these compelling advances in molecular biology research to the bedside. Through progress in the molecular understanding of hematology, great strides have been made in our ability to diagnose and treat patients with hematologic disease. These advances in turn have given rise to more questions that will guide future studies of the biology of hematopoietic abnormalities and continue the exciting interaction of basic science and clinical medicine.
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PMID:Introduction: molecular diagnostics in hematology. 1053 Jul 14

We describe previously transfused patients with sickle cell disease (n = 6) and thalassemia (n = 1) who received nonmyeloablative hematopoietic stem cell transplantation (HCT) to induce stable (full or partial) donor engraftment. Patients were 3 to 20 years (median, 9 years) old. All 7 received pretransplantation fludarabine and 200 cGy of total body irradiation; 2 patients also received horse antithymocyte globulin. Patients received bone marrow (n = 6) or peripheral blood stem cells (n = 1) from HLA-identical siblings, followed by a combination of mycophenolate mofetil and cyclosporine or tacrolimus for postgrafting immunosuppression. After nonmyeloablative HCT, absolute neutrophil counts were <0.5 x 10(9)/L and <0.2 x 10(9)/L for a median of 5 days (range, 0-13 days) and 0 days (range 0-13 days), respectively. A median of 0 (range, 0-9) platelet transfusions were administered. No grade IV nonhematologic toxicities were observed. One patient experienced grade II acute graft-versus-host disease. Two months after transplantation, 6 of 7 patients had evidence of donor chimerism (range, 25%-85%). Independent of red blood cell transfusions, these 6 patients initially had increased total hemoglobin and hemoglobin A concentrations and a reduction of reticulocytosis and transfusion requirements. There were no complications attributable to sickle cell disease during the interval of transient mixed chimerism. However, after posttransplantation immunosuppression was tapered, there was loss of the donor graft, and all patients experienced autologous hematopoietic recovery and disease recurrence. One patient did not engraft. The duration of transient mixed chimerism ranged from 97 to 441 days after transplantation in patients 4 and 6, respectively, and persisted until immunosuppressive drugs were discontinued after transplantation. In summary, the nonmyeloablative HCT regimens described here produced minimal toxicity and resulted in transient donor engraftment in 6 of 7 patients with hemoglobinopathies. Although complications from the underlying hemoglobinopathies did not occur during the period of mixed chimerism, these results suggest that stable (full or partial) donor engraftment after nonmyeloablative HCT is more difficult to achieve among immunocompetent pediatric patients with hemoglobinopathies than among adults with hematologic malignancies, perhaps in part because recipients may have been sensitized to minor histocompatibility antigens of their donor by preceding blood transfusions.
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PMID:Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and beta-thalassemia. 1293 Nov 21

Allogeneic bone marrow or blood stem cell transplantation (BMT) represents an important therapeutic tool for the treatment of an otherwise incurable broad spectrum of malignant and non-malignant diseases. Until recently, BMT was used primarily to replace a malignant, genetically abnormal or deficient immunohematopoietic compartment and therefore, highly toxic myeloablative regimens were considered mandatory for more effective eradication of all undesirable host-derived hematopoietic cells, including stem cells and their progeny. Our preclinical and ongoing clinical studies indicated that much more effective eradication of host immunohematopoietic system cells can be mediated by donor lymphocytes in the process of adoptive allogeneic cell therapy following BMT. Thus, eradication of all malignant cells, especially in patients with CML and, to a lesser extent, in patients with other hematologic malignancies can be accomplished despite complete resistance of puch tumor cells to maximally tolerated doses of chemoradiotherapy. Our cumulative experience suggested that graft-versus-malignancy effects might be used as a tool for eradication of otherwise resistant tumor cells of host origin. We speculated that the therapeutic benefit of BMT may be improved by using safer conditioning for engraftment of donor stem cells induce host-versus-graft unresponsiveness to enable engraftment of donor lymphocytes for subsequent induction of graft-versus-malignancy effects, or even graft-versus-autoimmunity and graft-versus-genetically abnormal cells. In other words, focusing on more selective and smarter rather than stronger modalities. Effective BMT procedures may be accomplished without lethal conditioning of the host, using a new, well-tolerated and user-friendly non-myeloablative regimen, thus eliminating or minimizing immediate and late procedure-related toxicity and mortality. It appears that initial induction of graft tolerance, mediated by engraftment of donor stem cells, leads to durable engraftment of immunocompetent donor lymphocytes, which may be necessary for induction of effective biologic warfare against host-type immunohematopoietic cells. Consequently, stem-cell therapy following induction of transplantation tolerance by selective elimination of alloreactive donor lymphocytes may represent the treatment of choice for a wide range of otherwise incurable diseases, including cancer (hematologic malignancies and certain metastatic solid tumors), genetic disorders (hemoglobinopathies and enzyme deficiency disorders), diseases caused by self-reactive lymphocytes (autoimmune diseases such as multiple sclerosis, rheumatoid arthritis) to mention just a few. Using reduced intensity conditioning, non-myeloablative stem cell transplantation (NST) can be accomplished with no major procedure-related toxicity or mortality. Thus, NST offers the feasibility of safe stem cell transplantation and cell-mediated procedures for a large and constantly growing spectrum of clinical indications for all patients in need without lower or upper age limit. Future strategies currently under investigation include developing new approaches for control of alloreactivity of host-versus-graft and graft-versus host reactivity reactions and developing better approaches for maximizing the capacity of donor lymphocytes to eliminate cancer cells more selectively, while avoiding or minimizing GVHD for safer and more effective treatment of patients in need of BMT.
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PMID:Reduced-intensity conditioning for the treatment of malignant and life-threatening non-malignant disorders. 1538 19

Allogeneic hematopoietic stem cell transplantation is a potentially curative treatment modality for a number of hematologic malignancies, as well as inherited immunodeficiencies and hemoglobinopathies, and may also have a role in selected acquired autoimmune disorders. The complete or near-complete ablation of host immunity and subsequent establishment of donor-derived immunity that is required for successful engraftment and long-term outcomes provide a major obstacle to such transplantation approaches. A delicate balance exists between the need for the reconstituted donor-derived immunity to provide both protection against pathogenic challenges and graft-versus-malignancy activity, and the potentially harmful expansion of alloreactive T-cell clones mediating GvHD. The search for interventions that would allow more rapid and selective reconstitution of beneficial immune specificities continues to be informed by the development of new tools enabling a more precise dissection of the kinetics of reconstituting populations. This review summarizes more recent data on immune reconstitution following allogeneic transplantation in humans.
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PMID:Reconstitution of adaptive and innate immunity following allogeneic hematopoietic stem cell transplantation in humans. 1705 Feb 47

Hematopoietic stem cells (HSCs) have the capacity for self-renewal and the potential to differentiate into all types of hematopoietic and immune system cells. These features have been successfully used to treat a multitude of hematologic malignancies and nonmalignant diseases such as aplastic anemia, hemoglobinopathies, inborn errors of metabolism and congenital immunodeficiency states. The application of HSC transplantation has been expanded over the past decade to include immune-mediated diseases such as multiple sclerosis, treatment-refractory rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. Transplantation of HSCs for the treatment of autoimmune diseases aims to fundamentally correct the dysregulated immune system, which could result in sustained clinical remission or potential cure. The use of this approach is currently restricted to clinical research, as there is no standard conditioning regimen to attain these aims in autoimmune diseases. HSC transplantation is associated with inherent morbidity and mortality, both treatment-related and disease-related, and selecting the correct group of patients with the best risk:benefit ratio is a challenging task.
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PMID:Technology Insight: hematopoietic stem cell transplantation for systemic rheumatic disease. 1828 64

Granulocyte colony-stimulating factor (G-CSF) has been reported to exacerbate vaso-occlusive crises in sickle cell disease. It has been recommended to avoid its use for stem cell mobilization in this population, yet autologous transplant is the standard of care and at times a life-saving treatment for patients with various hematologic malignancies such as relapsed aggressive lymphoma or multiple myeloma. We report 5 cases of patients with sickle cell disease and related hemoglobinopathies who underwent granulocyte-colony stimulating factor (G-CSF)-mobilization of peripheral blood stem cells (PBSC). Three of them developed manageable vaso-occlusive pain symptoms requiring parenteral narcotics alone. The 2 others had no complications. These cases demonstrate that stem cell mobilization using G-CSF, although complicated and not without risk, is feasible in patients with sickle cell syndromes.
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PMID:Granulocyte colony-stimulating factor-based stem cell mobilization in patients with sickle cell disease. 1848 98

The pyrimidine analogs, 5-azacytidine (azacitidine, Vidaza) and its deoxy derivative, 5-aza-2'-deoxycytidine (decitabine, Dacogen, are the most widely used inhibitors of DNA methylation which trigger demethylation leading to a consecutive reactivation of epigenetically silenced tumor suppressor genes in vitro and in vivo. Although the antileukemic capacity of decitabine has been known for almost 40 years, its therapeutic potential in hematologic malignancies is still under intensive investigation. Multiple clinical trials have shown the promising activity of low-dose decitabine in AML, MDS, CML, and hemoglobinopathies, whereas its efficacy in solid tumors is rather limited.Clinical responses appear to be induced by both epigenetic alterations and the induction of cell-cycle arrest and/or apoptosis. Recent clinical trials have been investigating new dosing schedules, routes of administration, and combination of decitabine with other agents, including histone deacetylase (HDAC) inhibitors.
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PMID:Decitabine. 2007 36

In the past half-century, hematopoietic stem cell transplantation has become standard treatment for a variety of diseases in children and adults, including selected hematologic malignancies, immunodeficiencies, hemoglobinopathies, bone marrow failure syndromes, and congenital metabolic disorders. There are 3 sources of allogeneic hematopoietic stem cells: bone marrow, peripheral blood, and umbilical cord blood; each has its own benefits and risks. Children often serve as hematopoietic stem cell donors, most commonly for their siblings. HLA-matched biological siblings are generally preferred as donors because of reduced risks of transplant-related complications as compared with unrelated donors. This statement includes a discussion of the ethical considerations regarding minors serving as stem cell donors, using the traditional benefit/burden calculation from the perspectives of both the donor and the recipient. The statement also includes an examination of the circumstances under which a minor may ethically participate as a hematopoietic stem cell donor, how the risks can be minimized, what the informed-consent process should entail, the role for a donor advocate (or some similar mechanism), and other ethical concerns. The American Academy of Pediatrics holds that minors can ethically serve as stem cell donors when specific criteria are fulfilled.
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PMID:Children as hematopoietic stem cell donors. 2010 Jul 53


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