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

作者：Komrokji Rami S; Mailloux Adam W; Chen Dung Tsa; Sekeres Mikkael A; Paquette Ronald; Fulp William J; Sugimori Chiharu; Paleveda Pena Jennifer; Maciejewski Jaroslaw P; List Alan F; Epling Burnette Pearlie K^*

来源：Haematologica-The Hematology Journal, 2014, 99(7): 1176-1183.

DOI：10.3324/haematol.2012.083345

Immune dysregulation is a mechanism contributing to ineffective hematopoiesis in a subset of myelodysplastic syndrome patients. We report the first US multicenter non-randomized, phase II trial examining the efficacy of rabbit(r)-anti-thymocyte globulin using 2.5 mg/kg/day administered daily for 4 doses. The primary end point was hematologic response; secondary end points included duration of response, time to response, time to progression, and tolerance. Nine (33%; 95% confidence interval=17%-54%) of the 27 patients treated experienced durable hematologic improvement in an intent-to-treat analysis with a median time to response and median response duration of 75 and 245 days, respectively. While younger age is the most significant factor favoring equine(e)-antithymocyte globulin response, treatment outcome on this study was independent of age (P=0.499). A shorter duration between diagnosis and treatment showed a positive trend (P=0.18), but International Prognostic Scoring System score (P=0.150), karyotype (P=0.319), and age-adjusted bone marrow cellularity (P=0.369) were not associated with response classification. Since activated T-lymphocytes are the primary cellular target of anti-thymocyte globulin, a T-cell expression profiling was conducted in a cohort of 38 patients consisting of rabbit and equine-antithymocyte globulin-treated patients. A model containing disease duration, CD8 terminal memory T cells and T-cell proliferation-associated-antigen expression predicted response with the greatest accuracy using a leave-one-out cross validation approach. This profile categorized patients independent of other covariates, including treatment type and age using a leave-one-out-cross-validation approach (75.7%). Therefore, rabbit-antithymocyte globulin has hematologic remitting activity in myelodysplastic syndrome and a T-cell activation profile has potential utility classifying those who are more likely to respond (NCT00466843 clinicaltrials.gov).

• 出版日期2014-7-1