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These findings suggest that discontinuation of second- or subsequent-line dasatinib after a sustained DMR of ≥ 1 year is feasible, especially for patients with no history of imatinib resistance. In addition, the natural killer cell count was associated with the TFR.

SummaryPeripheral blood from 489 recently diagnosed patients with aplastic anaemia (AA) and 316 with refractory anaemia (RA) of myelodysplastic syndrome was evaluated to characterize CD55

Category Clinical investigations Word countsTotal text word count: 3412 words Abstract word count: 240 words 2 ABSTRACTObjective. Although a number of reports have documented a significantly increased incidence of HLA-DR15 in aplastic anemia (AA), the exact role of HLA-DR15 in the immune mechanisms of AA remains unclear. We herein clarify the difference between DRB1*1501 and DRB1*1502, the 2 DRB1 alleles which determine the presentation of HLA-DR15, in the pathophysiology of AA. Materials and Methods.We investigated the relationships of the patients' HLA-DRB1 allele with both the presence of a small population of CD55 -CD59 -(PNH-type) blood cells and the response to antithymocyte globulin (ATG) plus cyclosporine (CsA) therapy in 140 Japanese AA patients. Results. Of the 30 different DRB1 alleles, only DRB1*1501 (33.6% vs. 12.8%, P c <0.01) and DRB1*1502 (43.6% vs. 24.4%, P c <0.01) displayed significantly higher frequencies among the AA patients than among a control. AA patients possessing HLA-DR15 tended to be old, and especially, the frequency of DRB1*1502 in patients ≥40 years old (52.4%) was markedly higher than that in those <40 years old (16.2%, P c <0.01). Only DRB1*1501 was significantly associated with the presence of a small population of PNH-type cells and it also showed a good response to ATG plus CsA therapy in a univariate analysis. A multivariate analysis showed only the presence of a small population of PNH-type cells to be a significant factor associated with a good response to the immunosuppressive therapy (P<0.01). Conclusion.Although both DRB1*1501 and DRB1*1502 contribute to the development of AA, the methods of contribution differ between the two alleles.3

Summary:To clarify the role of donor leukocyte infusion (DLI) in the treatment of leukemia relapsing after allo-BMT, data from 100 patients were collected from 46 facilities in Japan and analyzed with respect to the efficacy and adverse effects of donor leukocyte infusion. Complete remission was achieved in 11 of 12 (91%) patients with relapsed chronic myelogenous leukemia (CML) in chronic phase, three of 11 (27%) with CML in the acute phase, eight of 21 (38%) with acute myelogenous leukemia (AML), six of 23 (25%) with acute lymphoblastic leukemia (ALL) and five of 11 (45%) with myelodysplastic syndrome (MDS). The probability of remaining in CR at 3 years was 82% in CML patients in the chronic phase, but 0% in those with CML in the acute phase, 7% in those with AML, 0% with ALL and 33% with MDS. Acute GVHD (у2) developed in 31 of 89 (34%) patients with HLA-identical related donors and was fatal for seven (7%). Cytopenia developed in 21 of 94 (22%) with no associated fatalities. When the outcome of patients with CML in CP and MDS was analyzed, development of GVHD, cytopenia, or both, was associated with a higher GVL effect (15 of 16, 93%) than in those without adverse affects (one of 6, 17%). A leukocyte dose of 5 ؋ 10 7 /kg of recipient body weight appeared to be optimal as an initial dose of DLI. Given the relatively low incidence of acute GVHD and the similar GVL effect, DLI may be more beneficial to patients in Japan with recurrent leukemia than to those in Western countries. Bone Marrow Transplantation (2000) 26, 769-774. Keywords: DLI; GVL; outcome; Japanese; BMT Donor leukocyte infusion (DLI) has been established as a salvage therapy for patients with CML relapsing in the chronic phase after allogeneic BMT in Western countries. [1][2][3][4][5][6][7] Correspondence: Dr S Shiobara, Division of Transfusion Medicine, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa 920, Japan Received 21 February 2000; accepted 8 June 2000However, this adoptive immunotherapy is associated with the development of acute GVHD at a reported incidence of 59% to 90%. 5-9 Therefore, the beneficial effect of DLI can be offset by severe GVHD. 5.8.9 Since the incidence and severity of GVHD after BMT is reportedly low in Japanese patients, 10-12 the net effect of DLI may differ from that of BMT patients in Western countries. We therefore conducted a survey on the outcome of DLI in Japanese patients with recurrent leukemia. Materials and methods Data collectionIn November 1995, centers participating in the Japanese Group for Marrow Transplant Registry were asked to report all patients treated with donor leukocyte infusion. They were asked to report additional information regarding the outcome and new patients in November 1996 and in July 1998. Thus, we collected data regarding the outcomes of 108 patients from 46 centers. Data included patient age, sex, diagnosis, stage of disease at transplantation, donor characteristics, date of transplant, conditioning regimen, method of prophylaxis for GVHD, severity of acute and chronic GVH...

IntroductionAcquired aplastic anemia (AA), a bone marrow failure syndrome characterized by pancytopenia and bone marrow hypoplasia, has been the subject of study by hematologists for many years, as more than 70% of AA patients improve under immunosuppressive therapies such as antithymocyte globulin (ATG) and cyclosporine (CsA). [1][2][3] The dramatic effects of such T-cell suppressants on in vivo hematopoiesis suggest that immune system attack against hematopoietic stem cells plays an essential role in the development of AA. [4][5][6] However, despite extensive efforts to clarify the immune mechanisms of AA, the key antigens provoking immune response against hematopoietic stem cells remain unknown. This is largely due to a lack of animal models and the heterogeneity of pathogenesis in AA. Lack of good progenitor cell assays in humans has also hindered the elucidation of immune mechanisms in AA.In organ-specific autoimmune diseases, such as insulindependent diabetes mellitus (IDDM) and multiple sclerosis where autoreactive T cells play a primary role in pathogenesis, autoantibodies against target proteins of the pathogenic T cells are often detected. [7][8][9][10] Although such antibodies do not usually contribute to the pathogenesis of T-cell-mediated diseases, detection of the antibodies may prove useful in both identifying autoantigens and diagnosing immune mechanisms underlying the diseases. 11 We recently demonstrated that HLA-DRB1*1501 and increased paroxysmal nocturnal hemoglobinuria (PNH)-type cells represent prognostic markers for the immune mechanisms of AA. 12,13 Extensive investigation of antibodies in the sera of patients possessing HLA-DRB1*1501 and a minor population of PNH-type cells may be useful in identifying novel autoantigens in AA. Using immunofluorescent analysis, we previously found that antibodies to UT-7, a megakaryoblastic cell line, are frequently detectable in sera of AA patients who display increased PNH-type cells (PNH ϩ patients; unpublished observation, T.C. and S.N., May 2001). These antibodies may recognize antigens that elicit T-cell responses against hematopoietic stem cells, allowing expansion of PNH-type stem cells. 14,15 To examine these hypotheses, we screened proteins derived from UT-7 cDNA library using serum from a PNH ϩ patient with HLA-DRB1*1501. Serologic identification of antigens by recombinant expression cloning (SEREX) analysis identified diazepambinding inhibitor-related protein 1 (DRS-1) as an autoantigen that raises both antibody production and T-cell responses to antigenpresenting cells transfected with DRS-1 gene. AA and MDS were diagnosed in patients at Kanazawa University Hospital and other hospitals taking part in the bone marrow failure study group led by the Ministry of Health, Labor, and Welfare of Japan. MDS was diagnosed on the basis of cytopenia in peripheral blood, hypercellularity or normocellularity in the sternal or iliac bone marrow, and presence of dysplasia in at least 2 lineages of bone marrow cells. Cytogenetic abnormalities such as trisomy...

To clarify the pathologic significance of granulocytes exhibiting the paroxysmal nocturnal haemoglobinuria (PNH) phenotype in patients with aplastic anaemia (AA), we examined peripheral blood from 100 patients with AA for the presence of granulocytes deficient in glycosylphosphatidylinositol (GPI)-anchored proteins using a sensitive flow cytometric assay. A significant increase in the frequency of CD55-CD59-CD11b+ granulocytes (>0.003%) compared to normal individuals was observed in 31 of 35 (88.6%) patients with untreated AA at diagnosis. The proportions of patients showing increased PNH granulocytes in treated AA patients with a short (<5 yr) and long (>5 yr) disease duration were 68.6% (11/16) and 20.4% (10/49), respectively. When 19 patients showing increased frequency of PNH granulocytes before therapy were studied 6-12 months after antithymocyte globulin plus cyclosporin A therapy, the frequency decreased to 0.01-90% of pretreatment values in 15 recovering patients. These findings suggest that a relative increase in the number of PNH granulocytes is a common feature of AA at diagnosis, and that it may represent the presence of immunologic pressure to normal haematopoietic stem cells as a cause of AA.

Although increased blood cell deficiency of glycosyl phosphatidylinositol-anchored membrane proteins has often been detected in patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS), the clinical significance of such paroxysmal nocturnal hemoglobinuria (PNH)-type cells remains to be elucidated. We established a sensitive flow cytometric assay capable of detecting less than 0.01% of CD59-CD55- blood cells in a sample and used the assay to examine a large number of patients with bone marrow failure. An increase in the proportion of PNH-type cells was detectable in approximately 60% of all AA patients and in 20% of all refractory anemia (RA)-MDS patients. The increase was undetectable in patients with RA with an excessive number of blasts, acute myelogenous leukemia, multiple myeloma, or systemic lupus erythematosus. Our study showed that the presence of an increased number of PNH-type cells was predictive of a good response to immunosuppressive therapy and a favorable prognosis among patients with recently diagnosed AA and RA. A sensitive flow cytometric analysis for detection of a small population of PNH-type cells in peripheral blood cells is one of the most important examinations in the management of bone marrow failure.