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  • 1
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 3009-3009
    Abstract: Allogeneic stem cell transplantation produces a strong graft-versus-leukemia effect which may be enhanced by HLA-mismatches and immune recognition as a result of pregnancy. Therefore we compared the results of HLA-haploidentical transplantation (N=113) to those of HLA-identical sibling (N=195) transplantation performed in the same time. Cases were matched by disease category (acute myeloid leukemia-myelodysplastic syndromes, AML/MDS, acute lymphoid leukemia ALL and lymphoma-chronic lymphocytic leukemia NHL/CLL) and stage of the disease (early, intermediate and advanced). HLA-haploidentical transplants were performed with unmodified bone marrow followed by CD6-depleted mobilized blood stem cells on day 6.; patients with leukemia were in more advanced disease in leukemia, they were younger and more often male. In multivariate analysis survival was influenced by HLA-mismatch, stage of the disease and age of the patient, but conditioning treatment and CMV-seropositivity had no significant effect. Transplant related mortality was influenced by the age of the patient and HLA-match, to a lesser extent by the disease category and the stage, whereas CMV-seropositivity and conditioning had no influence. Remission duration was dependent on the stage of the disease, the donor recipient gender combination and the conditioning treatment in univariate analysis; in multivariate analysis only CMV-seropositivity had a poor prognostic impact. In comparable disease stages the relapse rate was not different in HLA-haploidentical from HLA-identical transplantation as was the rate of acute GVHD. In contrast the rate of chronic GVHD was lower in HLA-haploidentical transplantation. In ALL, relapse rate and remission duration was inferior with non-myeloablative conditioning as compared to myeloablative total body irradiation. In HLA-haploidentical transplantation the response rate of leukemia was better in patients homozygous for the cross reactive HLA-C group given a transplant from a heterozygous donor suggestive of NK activity. This GVL activity was not associated with GVH activity. Similarly maternal donors were superior to paternal donors and female donors in male recipients better than other gender combinations for the control of leukemia without increased GVHD. Non-inherited maternal antigen (NIMA) and inherited paternal antigen (IPA) in the graft-vs-host direction had a weak influence on the relapse rate, but no influence on GVHD. On an observational basis several sons and daughters transplanted with stem cells from the mother had a strong GVL effect without any signs of GVHD. However two have been lost due to untreatable pulmonary complications. Donors with cytotoxic antibodies have been excluded from donation, but cellular reactivity will have to be assessed in more detail. Recent progress in controlling EBV-associated disease by selection of donor T cells without expansion will improve HLA-haploidentical transplantation and show the way to selecting donor with the appropriate immune repertoire including reactivity to leukemia.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 2
    In: Blood, American Society of Hematology, Vol. 115, No. 14 ( 2010-04-08), p. 2960-2970
    Abstract: Posttransplantation lymphoproliferative disease (PTLD) associated with Epstein-Barr virus (EBV) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation. PTLD is efficiently prevented by adoptive transfer of EBV-specific T cells from the donor. To make EBV-specific T cells available in urgent clinical situations, we developed a rapid protocol for their isolation by overnight stimulation of donor blood cells with peptides derived from 11 EBV antigens, interferon-γ surface capture, and immunomagnetic separation. Six patients with PTLD received 1 transfusion of EBV-specific T cells. No response was seen in 3 patients who had late-stage disease with multiorgan dysfunction at the time of T-cell transfer. In 3 patients who received T cells at an earlier stage of disease, we observed complete and stable remission of PTLD. Two patients have remained free from EBV-associated disease for more than 2 years. CD8+ T cells specific for EBV early antigens rapidly expanded after T-cell transfer, temporarily constituted greater than 20% of all peripheral blood lymphocytes, and were maintained throughout the observation period. Thus, a rapid and sustained reconstitution of a protective EBV-specific T-cell memory occurred after the infusion of small numbers of directly isolated EBV-specific T cells.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 978-978
    Abstract: Allogeneic stem cell transplantation is limited to patients with a histocompatible donor, but for patients with advanced acute leukemia and high-grade lymphoma HLA-haploidentical transplantation may be considered. Rejection of the transplant and graft-versus-host disease are major obstacles and T-cell depletion eliminates the graft-versus-leukemia effect and causes prolonged immune deficiency. Here we studied the use of CD6-depleted G-CSF mobilized blood cells (mbc) 6 days after transplantation of unmodified marrow in order to suppress host-versus-graft and graft-versus-host reactions (GVHD) retaining a graft-versus-leukemia effect and the capacity to reconstitute the immune system. CD6-depleted mbc contain a large proportion of NK and NK-T cells. 63 patients with advanced disease (AML 32, ALL 15, NHL 11, CLL 2, CML 2, SAA 1) were transplanted with marrow from family donors sharing one HLA-haplotype and differing in 0 – 4 HLA-antigens of the second haplotype. Conditioning consisted of total body irradiation (TBI), antithymocyte globulin (ATG) and cyclophosphamide (CY), post-grafting immunosuppression of cyclosporin A (CSA) and a short course of methotrexate (sMTX). A transfusion of donor leukocytes was given prior to CY. Complete engraftment was observed in 34 evaluable patients given 12 Gy TBI. The dose of TBI could be reduced to 4 Gy without rejection in 25 evaluable patients. GVHD was severe (grade III and IV) in 12 of 48 evaluable patients. An improved method of CD6-depletion was administered to mbc in 9 patients and severe GVHD did not develop. GVHD responded to corticosteroids in most patients. 15 patients survive disease free up to 6 years (median 784 days). Recurrent infections including PTLD were the major cause of transplant-related mortality. Absolute counts of lymphocytes, CD4 and CD8 subpopulations were not different from those of a contemporary group of 46 patients in advanced disease given HLA-identical sibling transplants. However naïve CD4 cells and TRECs were low. Rejection, GVHD and GVL have been controlled by this regimen, but immune reconstitution remains a problem that may be solved by early discontinuation of immunosuppression in this regimen.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    Online Resource
    Online Resource
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 2151-2151
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 2151-2151
    Abstract: Acute graft-versus-host disease (aGVHD) is a major obstacle of allogeneic stem cell transplantation (SCT). We compared a cohort of 58 patients with HLA-haploidentical transplants (haplo) and a contemporary group of 229 patients with HLA-identical transplants (id) for the manifestation of aGVHD. Haplo-patients were given unmodified marrow (bm) and CD6- depleted mobilized blood cells (mbc) 6 days after marrow transplantation. The combination of cyclosporin A (CSA) and a short course of methotrexate (sMTX) was given post-grafting. Standard intensity conditioning was given to 34 and reduced intensity conditioning to 24 patients. Id-patients were given bm in 140, mbc in 79 and the combination of bm and mbc in 6 cases. Post grafting immunosuppression consisted of CSA either alone (N=10) or in combination with sMTX (N=158), and/or mycophenolate mofetil (MMF) (N=57). Conditioning was of reduced intensity in 50 patients and standard in 175 patients. Haplo-patients were younger in age (34 vs. 44 yrs.), more frequently male and in a more advanced stage of their disease. Manifestations of aGVHD, microangiopathy characterized by schistocytes and elevated LDH and virus infections were evaluated. Haplo-patients had more severe aGVHD of the skin than id-patients (IBMTR index B – D: 53% vs. 37%; p 〈 0.02). Response to the treatment with corticosteroids was better in haplo-patients than in id-patients (74% vs. 52%; p =0.048). Extensive chronic GVHD was less frequent in haplo-patients than id-patients (14% vs. 39%; p=0.005). However virus infections requiring virostatic therapy were more frequent in haplo-patients (60% vs. 40%; p=0.03). Modification of aGVHD has been achieved by transfusion of CD6-depleted mbc 6 days after transplantation of unmodified bm. CD6-depleted mbc contain non-specific suppressor cells. Improved depletion has eliminated severe aGVHD (IBMTR C & D) completely. However immune deficiency and recurrent viral infections remain a problem.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 2907-2907
    Abstract: Allogeneic stem cell transplantation from HLA-haploidentical family members has been studied in 80 patients for the treatment of hematological malignancies in advanced stages. The protocol involves unmodified marrow on day 0 and CD6-depleted G-CSF-mobilized blood cells on day 6. Engraftment was seen in patients treated with myeloablative (12 Gy) and non-myeloablative (4 Gy) doses of total body irradiation. Graft-versus-host disease (GVHD) was mild or absent in 53% and severe GVHD did not develop after changing to a more effective method of depletion of CD6-positive cells. Acute GVHD resolved more often and chronic GVHD was less severe than in HLA-identical sibling transplantation. Here we evaluated survival and relapse risk. Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) was the diagnosis in 41 patients, acute lymphoid leukemia (ALL) in 19 patients, chronic myelogenous leukemia (CML) in 2, chronic lymphocytic leukemia (CLL) in 3, high grade lymphoma (NHL) in 14 and severe aplastic anemia (SAA) in one patient. The patient’s age ranged from 17 to 62 years (median 36.5 yrs), for 65 patients a relative of first degree and for 15 patients a second degree relative was the donor. The major cause of death was recurrence of the disease (29 pts.), 7 patients died early and 22 pts. died of complications (infections 12, GVHD 3, pulmonary compl. 2, PTLD 3, cerebr. hemorrhage 1, liver tox. 1). Survival was significantly better in male patients with female donors (2 yr survival 36% vs 13%; p=0.001), patients transplanted with cells from their mother rather than from the father (2 yr survival 55% vs 8%; p=0.02) and patients transplanted in an earlier phase (2yr survival 50% vs 15%; p=0.048). Patients transplanted for ALL (2 yr. survival 31%) fared better than patients with AML/MDS (2yr survival 23%)and patients with NHL (2 yr. survival 12.5%) (p=0.08). Age, number and type of HLA-mismatches, as well as the depletion method had no effect on survival and on relapse risk. The favorable effect of the female gender of the donor on survival was still significant in multivariate analysis after adjustment for the stage of the disease and the diagnosis (p=0.01). The possibility of non-inherited maternal antigens (NIMA) inducing tolerance was tested in siblings sharing the paternal haplotype. There was a weak effect in the host-versus-graft direction (p=0.06), but no effect in the graft-versus-host direction. The risk of relapse was lowest in patients transplanted with stem cells from their mother as compared to those transplanted from their father (p=0.002). Female gender of the donor was favorable even in patients without GVHD. In summary female donors are preferable to male donors for control of leukemia and survival.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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