Immunosuppressive therapies in the management of acquired immune-mediated marrow failures

Risitano, Antonio M.

doi:10.1097/moh.0b013e32834da9a4

Cited by 17 publications

(10 citation statements)

References 73 publications

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“…33 In early MDS, altered T-cell populations may directly suppress hematopoiesis since both CD8 + and CD4 + T cells have the capacity to damage bone marrow by cellcell mediated interactions, by the Fas/Fas receptor apoptotic pathway, or release of inhibitory cytokines including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) or transforming growth factor-β (TGF-β). 34 The presence of autoreactive or damaging effector T cells are a stimulus for highly suppressive regulatory populations such as myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs). 35 Recent evidence shows that MDSCs contribute to the dysplastic phenotype 36 and Tregs are a risk factor for disease progression 37,38 in MDS.…”

Section: Discussionmentioning

confidence: 99%

A phase II multicenter rabbit anti-thymocyte globulin trial in patients with myelodysplastic syndromes identifying a novel model for response prediction

et al. 2014

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ABSTRACTresponsive to IST, development of cohesive selection criteria based on biological features, and optimizing treatment regimens are all key to adoption of this therapy for those MDS patients most likely to benefit. To this end, we performed a multicenter phase II trial to investigate the efficacy and safety of r-ATG in low or intermediate IPSS risk MDS patients, and analyzed pretreatment clinical variables associated with response. Combined data from this study and a second cohort of patients treated with e-ATG was analyzed to develop a cohesive biomarker-based model based on cytometry expression profiles to improve IST selection for MDS patients. Methods Patients and eligibility criteriaThis was a multicenter phase II clinical study. Details of patient eligibility criteria are available in the Online Supplementary Appendix. This trial (BMF RDCRN 5406) received institutional review board approval at all participating sites, and was registered at clinicaltrial.gov (NCT00466843). Drug administrationPatients were hospitalized to receive r-ATG (Thymoglobulin ® , Genzyme Corp) at a dose of 2.5 mg/kg/day intravenously (IV) for 4 doses (total 10 mg/kg). The daily infusion was administered over at least six hours and slowed as necessary to minimize infusionrelated symptoms, as detailed in the Online Supplementary Appendix. All patients were pre-medicated with prednisone (1 mg/kg/day orally) two days prior to the first dose and during the infusion, and then continued on a tapering schedule of prednisone for 14 days after the final r-ATG dose to prevent serum sickness.

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Section: Discussionmentioning

confidence: 99%

A phase II multicenter rabbit anti-thymocyte globulin trial in patients with myelodysplastic syndromes identifying a novel model for response prediction

et al. 2014

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“…Thus, several immunosuppressive agents in combination with ATG were explored to improve hematological response, sustain such response for longer period, and prevent subsequent relapse. In the 1990s, the combination of cyclosporine (CSA) with ATG was proven effective in increasing the response rate and survival [9], [10], which has been considered standard first-line IST for SAA with a 60–70% response rate and 70–80% long-term survival probability [11], [12], [13], [14].…”

Section: Introductionmentioning

confidence: 99%

Outcomes of Optimized over Standard Protocol of Rabbit Antithymocyte Globulin for Severe Aplastic Anemia: A Single-Center Experience

Shi

et al. 2013

PLoS ONE

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BackgroundPrevious reports showed that outcome of rabbit antithymocyte globulin (rATG) was not satisfactory as the first-line therapy for severe aplastic anemia (SAA). We explored a modifying schedule of administration of rATG.Design and MethodsOutcomes of a cohort of 175 SAA patients, including 51 patients administered with standard protocol (3.55 mg/kg/d for 5 days) and 124 cases with optimized protocol (1.97 mg/kg/d for 9 days) of rATG plus cyclosporine (CSA), were analyzed retrospectively.ResultsOf all 175 patients, response rates at 3 and 6 months were 36.6% and 56.0%, respectively. 51 cases received standard protocol had poor responses at 3 (25.5%) and 6 months (41.2%). However, 124 patients received optimized protocol had better responses at 3 (41.1%, P = 0.14) and 6 (62.1%, P = 0.01). Higher incidences of infection (57.1% versus 37.9%, P = 0.02) and early mortality (17.9% versus 0.8%, P<0.001) occurred in patients received standard protocol compared with optimized protocol. The 5-year overall survival in favor of the optimized over standard rATG protocol (76.0% versus. 50.3%, P<0.001) was observed. By multivariate analysis, optimized protocol (RR = 2.21, P = 0.04), response at 3 months (RR = 10.31, P = 0.03) and shorter interval (<23 days) between diagnosis and initial dose of rATG (RR = 5.35, P = 0.002) were independent favorable predictors of overall survival.ConclusionsOptimized instead of standard rATG protocol in combination with CSA remained efficacious as a first-line immunosuppressive regimen for SAA.

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“…The pathogenesis of AA is very complicated and the impaired hematopoiesis from bone marrow was reported to be related with abnormal numbers and functions of T lymphocytes as well as dysregulation of cytokine secretion, suggesting that AA was an autoimmune disease, characterized by increased Th1 cells and downstream cytokines [2–4]. T-bet (T-box expressed in T cell), a member of T-box family discovered in 2000, is a Th1-specific transcription factor, responsible for Th1 cell differentiation [5].…”

Section: Introductionmentioning

confidence: 99%

OCH Ameliorates Bone Marrow Failure in Mice via Downregulation of T-Bet Expression

Qiao

Xie

Shi

et al. 2014

Journal of Immunology Research

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The aim of this study is to evaluate the immune mechanism of OCH in the treatment of AA (also named bone marrow failure, BMF) induced in mice. OCH at a dose of 400 μg/kg was injected intraperitoneally (I.P.) prior to the induction of BMF. Our study showed that the incidence of BMF was 100% in BMF group and 13% in OCH treatment group. Significant higher level of IL-4 and lower level of IFN-γ were observed in OCH group than that in BMF group (P < 0.05) as well as untreated group over BMF (P < 0.05). However, there was no significant difference between OCH and untreated group. Compared with untreated, the expression level of T-bet in OCH and BMF was all significantly higher. However, T-bet expression level was lower in OCH than in BMF. In addition, OCH treatment increased NKT cell fractions of bone marrow and the colonies of CFU-GM. In conclusion, treatment of OCH prior to the induction of BMF could prevent the incidence of BMF possibly through downregulating T-bet expression leading to the transition of immune response from Th1 to Th2, suggesting OCH might be a new therapeutic approach in the treatment of BMF or AA.

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Immunosuppressive therapies in the management of acquired immune-mediated marrow failures

Cited by 17 publications

References 73 publications

A phase II multicenter rabbit anti-thymocyte globulin trial in patients with myelodysplastic syndromes identifying a novel model for response prediction

A phase II multicenter rabbit anti-thymocyte globulin trial in patients with myelodysplastic syndromes identifying a novel model for response prediction

Outcomes of Optimized over Standard Protocol of Rabbit Antithymocyte Globulin for Severe Aplastic Anemia: A Single-Center Experience

OCH Ameliorates Bone Marrow Failure in Mice via Downregulation of T-Bet Expression

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