Bone Marrow Graft in Man after Conditioning by Antilymphocytic Serum

Mathé, G; Amiel, J. L.; Schwarzenberg, L; Choay, J; Trolard, P; Schneider, M.; Hayat, M.; Schlumberger, Jean; Jasmin, C

doi:10.1136/bmj.2.5702.131

Cited by 195 publications

(60 citation statements)

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“…Autologous recovery of hematopoiesis in patients who failed to engraft after conditioning and stem cell transplantation, as well as responsiveness of patients to immunosuppressive therapies, 1 provided evidence of the pivotal role of the immune system in the disease pathophysiology. Treatment strategy is based on severity of the disease, patient age and availability of an HLA-identical related donor.…”

Section: Introductionmentioning

confidence: 99%

Long-term follow up after allogeneic stem cell transplantation in patients with severe aplastic anemia after cyclophosphamide plus antithymocyte globulin conditioning

Konopacki¹,

Porcher²,

Robin³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundDue to increased rates of secondary solid organ cancer in patients with severe aplastic anemia who received an irradiation-based conditioning regimen, we decided some years ago to use the combination of cyclophosphamide and antithymocyte globulin. We report the long-term follow up of patients who underwent hematopoietic stem cell transplantation from an HLAmatched sibling donor after this conditioning regimen. Design and MethodsWe analyzed 61 consecutive patients transplanted from June 1991 to February 2010, following conditioning with cyclophosphamide (200 mg/kg) and antithymocyte globulin (2.5 mg/kg/day x 5 days). ResultsMedian age was 21 years (range 4-43); 41 of the 61 patients were adults. Median duration of the disease before hematopoietic stem cell transplantation was 93 days. All but 2 patients received bone marrow as the source of stem cells and all but 2 engrafted. Cumulative incidence of acute grade II-IV graft-versus-host disease was 23% (95%CI 13-34) and 18 developed chronic graft-versus-host disease (cumulative incidence 32% at 72 months, 95% CI 20-46). In multivariate analysis, a higher number of infused CD3 cells was associated with an increased risk of developing chronic graft-versus-host disease (P=0.017). With a median follow up of 73 months (range 8-233), the estimated 6-year overall survival was 87% (95% CI 78-97). At 72 months, the cumulative incidence of avascular necrosis was 21% and 12 patients presented with endocrine dysfunction (cumulative incidence of 19%). Only one patient developed a secondary malignancy (Hodgkin's lymphoma) during follow up. ConclusionsCyclophosphamide and antithymocyte globulin is an effective conditioning regimen for patients with severe aplastic anemia and is associated with low treatment-related mortality. Long-term complications include avascular necrosis and endocrine dysfunction.Key words: hematopoietic stem cell transplantation, severe aplastic anemia, long-term outcomes. Haematologica 2012;97(5):710-716. doi:10.3324/haematol.2011 This is an open-access paper. Citation: Konopacki J, Porcher R, Robin M, Bieri S, Cayuela J-M, Larghero J, XhaardLong-term follow up after allogeneic stem cell transplantation in patients with severe aplastic anemia after cyclophosphamide plus antithymocyte globulin conditioning

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Section: Introductionmentioning

confidence: 99%

Long-term follow up after allogeneic stem cell transplantation in patients with severe aplastic anemia after cyclophosphamide plus antithymocyte globulin conditioning

Konopacki¹,

Porcher²,

Robin³

et al. 2011

Haematologica

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“…Historically, the unexpected improvement of hematopoietic function in some aplastic anemia (AA) patients failing engraftment after bone marrow transplantation 1 led to the systematic application of immunosuppressive therapies, with the majority of the patients now showing hematologic recovery without transplantation. [2][3][4] Many laboratory data has been accumulated to support an immunologic mechanism in idiopathic AA.…”

Section: Introductionmentioning

confidence: 99%

Oligoclonal and polyclonal CD4 and CD8 lymphocytes in aplastic anemia and paroxysmal nocturnal hemoglobinuria measured by Vβ CDR3 spectratyping and flow cytometry

Risitano

Kook

Zhang

et al. 2002

Blood

122

117

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SUMMARYWe have hypothesized that in aplastic anemia (AA) the presence of antigen-specific T-cells is reflected by their contribution to the expansion of a particular variable beta chain (V ) subfamily and also by clonal CDR3 skewing. To determine the role of disease-specific "signature" T-cell clones in AA, we studied preferential Vusage by flow cytometry and analyzed V -CDR3 regions for the presence of oligoclonality. We first established the contribution of each V family to the total CD4+ and CD8+ lymphocyte pool; in AA and PNH, a seemingly random over-representation of different V families was observed. On average, we found expansion in 3 (out of 22 examined) V families per patient. When the contribution of individual V families to the effector pool was examined, more striking V -skewing was found. V -CDR3 size distribution was analyzed for the expanded V families in isolated CD4+ and CD8+ populations; under-represented V families displayed more pronounced CDR3 skewing. Expanded CD4+V subfamilies showed mostly a polyclonal CDR3 size distribution with only 38% of skewing in expanded V families. In contrast, within over-represented CD8+V types, marked CDR3 skewing (82%) was seen, consistent with non-random expansion of specific CD8+ T-cell clones. No preferential expansion of particular V families was observed, in relation with HLA-type. In patients examined before and after immunosuppressive therapy, an abnormal V -distribution pattern was retained, but the degree of expansion of individual V was lower. As V -skewing may correlate with relative V size, oligoclonality in combination with numerical V expansion can be applied to recognition of disease-specific TCR.

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“…[1][2][3] Several studies have confirmed immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine (CyA) as a promising therapeutic option for patients lacking HLA-identical related donors. [4][5][6][7][8] Although several potential markers of IST response that appear to reflect the immune pathophysiology of aplastic anemia have been suggested, mainly from adult studies, [9][10][11] none have been widely accepted.…”

Section: Introductionmentioning

confidence: 99%

Predicting response to immunosuppressive therapy in childhood aplastic anemia

Yoshida¹,

Yagasaki²,

Hama³

et al. 2011

Haematologica

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9/L or more (P=0.0003), followed by shorter interval between diagnosis and therapy (P=0.01), and male sex (P=0.03). In conclusion, pre-treatment clinical and laboratory findings influence response to therapy. The finding that response rate worsens with increasing interval between diagnosis and treatment highlights the importance of prompt immunosuppressive therapy for patients with aplastic anemia.Key words: aplastic anemia, children, immunosuppressive therapy, predictive marker.Citation: Yoshida N, Yagasaki H, Hama A, Takahashi Y, Kosaka Y, Kobayashi R, Yabe H, Kaneko T, Tsuchida M, Ohara A, Nakahata T, Kojima S. Predicting response to immunosuppressive therapy in childhood aplastic anemia. Haematologica 2011;96(05):771-774. doi:10.3324/haematol.2010 This is an open-access paper. ABSTRACT ISTAll patients were treated with a combination of intravenous ATG (Lymphoglobulin; Genzyme, Cambridge, USA) at 15 mg/kg/day for five days and oral CyA at 6 mg/kg/day. The dose of CyA was adjusted to maintain trough levels between 100 and 200 ng/mL, and the appropriate dose was administered for at least six months. Granulocyte colony-stimulating factor (Filgrastim; Kirin, Tokyo, Japan) was administered intravenously or subcutaneously at 400 mg/m 2 for three months only to patients with very severe disease. 17 Response to IST was evaluated at six months after initiation of therapy. Complete response (CR) was defined as a neutrophil count more than 1.5×10 9 /L, a platelet count more than 100×10 9 /L, and a hemoglobin level more than 11.0 g/dL.17 Partial response (PR) was defined as a neutrophil count more than 0.5×10 9 /L, a platelet count more than 20×10 9 /L, and a hemoglobin level more than 8.0 g/dL in patients with severe or very severe AA, and as a neutrophil count more than 1.0×10 9 /L, a platelet count more than 30 ×10 9 /L, and a hemoglobin level more than 8.0 g/dL in patients with moderate AA.17 Overall response was defined as CR or PR at six months after IST. Statistical analysesParameters for univariate analyses to determine predictors of response to IST included age at diagnosis, sex, interval between diagnosis and treatment, etiology, severity of disease, white blood cell (WBC) count, neutrophil count, lymphocyte count, hemoglobin level, reticulocyte count, and platelet count. Pre-treatment laboratory values were defined as the lowest value without transfusions during the four weeks preceding IST. Continuous variables were divided into quartile categories, and these cut offs were used for categorical analysis. To evaluate correlations between these parameters and response, differences in continuous variables were analyzed using the Mann-Whitney U-test and differences in frequencies were tested using the χ 2 or Fisher's exact test. For multivariate analyses, logistic regression modeling was performed. Important covariates in the multivariate models were chosen using stepwise variable selection procedures. Values of P<0.05 were considered statistically significant. Results and DiscussionPatients' characteristics ...

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Bone Marrow Graft in Man after Conditioning by Antilymphocytic Serum

Cited by 195 publications

References 10 publications

Long-term follow up after allogeneic stem cell transplantation in patients with severe aplastic anemia after cyclophosphamide plus antithymocyte globulin conditioning

Long-term follow up after allogeneic stem cell transplantation in patients with severe aplastic anemia after cyclophosphamide plus antithymocyte globulin conditioning

Oligoclonal and polyclonal CD4 and CD8 lymphocytes in aplastic anemia and paroxysmal nocturnal hemoglobinuria measured by Vβ CDR3 spectratyping and flow cytometry

Predicting response to immunosuppressive therapy in childhood aplastic anemia

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