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Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases.

Myeloablative conditioning associated with hazardous immediate and late complications is considered as a mandatory first step in preparation for allogeneic blood or marrow transplantation (allogeneic BMT) for the treatment of malignant hematologic disorders and genetic diseases. Immune-mediated graft-versus-leukemia (GVL) effects constitute the major benefit of allogeneic BMT. Therefore, we have introduced the use of relatively nonmyeloablative conditioning before allogeneic BMT aiming for establishing host-versus-graft tolerance for engraftment of donor immunohematopoietic cells for induction of GVL effects to displace residual malignant or genetically abnormal host cells. Our preliminary data in 26 patients with standard indications for allogeneic BMT, including acute leukemia (n = 10); chronic leukemia (n = 8), non-Hodgkin's lymphoma (n = 2), myelodysplastic syndrome (n = 1), multiple myeloma (n = 1), and genetic diseases (n = 4) suggest that nonmyeloablative conditioning including fludarabine, anti-T-lymphocyte globulin, and low-dose busulfan (8 mg/kg) is extremely well tolerated, with no severe procedure-related toxicity. Granulocyte colony-stimulating factor mobilized blood stem cell transplantation with standard dose of cyclosporin A as the sole anti-graft-versus-host disease (GVHD) prophylaxis resulted in stable partial (n = 9) or complete (n = 17) chimerism. In 9 patients absolute neutrophil count (ANC) did not decrease to below 0.1 x 10(9)/L whereas 2 patients never experienced ANC < 0.5 x 10(9)/L. ANC > or = 0.5 x 10(9)/L was accomplished within 10 to 32 (median, 15) days. Platelet counts did not decrease to below 20 x 10(9)/L in 4 patients requiring no platelet support at all; overall platelet counts > 20 x 10(9)/L were achieved within 0 to 35 (median 12) days. Fourteen patients experienced no GVHD at all; severe GVHD (grades 3 and 4) was the single major complication and the cause of death in 4 patients, occurring after early discontinuation of cyclosporine A. Relapse was reversed by allogeneic cell therapy in 2/3 cases, currently with no residual host DNA (male) by cytogenetic analysis and polymerase chain reaction. To date, with an observation period extending over 1 year (median 8 months), 22 of 26 patients (85%) treated by allogeneic nonmyeloablative stem cell transplantation are alive, and 21 (81%) are disease-free. The actuarial probability of disease-free survival at 14 months is 77.5% (95% confidence interval, 53% to 90%). Successful eradication of malignant and genetically abnormal host hematopoietic cells by allogeneic nonmyeloablative stem cell transplantation represents a potential new approach for safer treatment of a large variety of clinical syndromes with an indication for allogeneic BMT. Transient mixed chimerism which may protect the host from severe acute GVHD may be successfully reversed postallogeneic BMT with graded increments of donor lymphocyte infusions, thus resulting in eradication of malignant or genetically abnormal progenitor cells of host origin.

Adolescent↗

The sexuality of patients with onco-hematological diseases.

We interviewed 20 patients staying at a hospital unit, by means of a data collection instrument that is based on the eclectic model, with a view to characterizing the biological, psychological and sociocultural aspects involving human sexuality which are affected in patients with onco-hematological diseases. The research complied with ethical requirements for studies involving human beings. The results revealed that these clients presented problems related to biological aspects, mainly with respect to the phase of sexual desire (60% of the sample), sexual excitation (75%) and orgasm (75%). The psychological aspects related to sexual self-image were affected in 60% of the sample; problems related to social aspects (85%) were mainly due to the fear of acquiring an infection as a result of the low immunity provoked by the disease and treatment. These clients demonstrated alterations in their sexual function and in the way they expressed their sexuality.

Adolescent↗

[Cytogenetic studies on 334 myelodysplastic syndrome (MDS), aplastic anemia (AA) and other hematological diseases].

In order to distinguish various types of MDS, such as RA/AA, RA/ITP or RA/HA, from AA, ITP or HA, bone marrow (BM) cells were studied by using cytogenetic techniques including R-banding karyotypic analysis and sister chromatid differentiation (SCD) assay in 334 cases of hematological diseases (160 MDS, 54 RA/AA, RA/ITP or RA/HA; 60 AA, 3 other known anemias, 38 PNH and 19 ITP). The results showed: (1) karyotypes and SCD values were both normal in more than 90% of AA, PNH, ITP and other known anemias, but they were both abnormal in about 35.6% of MDS and only 13.0% of RA/AA, RA/ITP or RA/HA. These results indicated that cytogenetic techniques were useful in hematological clinic and that RA/AA, or RA/ITP or RA/HA might be pre-RA or atypic RA. This was supported by the results of following up on some RA/AA, RA/ITP or RA/HA cases, (2) clonal abnormal karyotypes were found in 64.4% of MDS. The recurrent chromosomal alterations were +8, 20q-, -5/5q-, -7/7q-, similar to those reported in literatures. (3) 16 MDS cases were followed up and 15 MDS with SCD negative, but one with SCD positive developed leukemia in our hospital. It is suggested that change from SCD positive to negative was indicative of malignant transformation of BM cells. This was supported by the results of cytogenetic analysis in RA/AA, RA/ITP, RA, RAEB, RAEBT and leukemias. (4) Because more structural chromosome alterations occur in SCD negative than SCD positive MDS, the numerous chromosome alterations (monosomy) might occur in earliest development of MDS into leukemias.

Adolescent↗

Future approaches for treating hematologic disease.

The approval of monoclonal antibodies for therapy of hematologic malignacies (Rituxan, Mylotarg, Campath) renewed the interest in antibodies as potential new treatment options for cancer patients. Antibodies are effective in inhibiting tumor cell growth , inducing apoptosis, and activating host effector mechanisms for tumor cell killing. Monoclonal antibodies can be clinically effective as monotherapy, as targeting agents delivering either potent cytotoxic drugs or radionuclides as well as in combination with conventional chemotherapies. Advances in antibody engineering provided new capabilities to reduce immunogenicity, alter half life, increase effector functions, and increase tumor targeting for optimal therapeutic modalities requiring chronic dosing regimens. During the next decade, as new tumor-specific surface antigens are discovered and the linkage between genes and function is better understood, new targets will be identified for regulating tumor cell growth by engineered antibodies with agonist or antagonist activity. Additionally, antibody engineering will allow for more efficient radionuclide or cytotoxic drug targeting or lead to more selective activation of relevant host effector mechanisms, leading to a safe and effective therapy of cancer.

Animals↗

[Lysozyme in hematologic diseases].

Blood lysozyme estimation seems to be important in hematological practice. Serum levels are roughly proportional to the size of the pool and, above all, granulocytic renewal. Thus levels are increased compared with levels of circulating polynuclear cells. In bone marrow disorders, and particularly in myelofibrosis, owing to the infective granulopoiesis and/or increased destruction of the neutrophil polymorphs. It is lowered in neutropenia with a scanty bone marrow. It provides an important contribution to diagnosis of the type of acute leukemia, the fall in the lymphoblastic forms contrast with normal or increased levels in myeloblastic forms. Finally, there is a marked increase in lysosome urea in acute monocytic or myelomonocytic leukemia.

Anemia↗