A phase II multicenter rabbit anti-thymocyte globulin trial in patients with myelodysplastic syndromes identifying a novel model for response prediction.
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)-anti-thymocyte 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-anti-thymocyte 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).
Malignant Hematology Division, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
Rami S
RS
Komrokji
Immunology Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
Adam W
AW
Mailloux
Biostatistics Program, H. Lee H. Lee Moffitt Cancer Center, Tampa, FL, USA.
Dung-Tsa
DT
Chen
Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.
Mikkael A
MA
Sekeres
UCLA Medical Center, Los Angeles, CA, USA.
Ronald
R
Paquette
Biostatistics Program, H. Lee H. Lee Moffitt Cancer Center, Tampa, FL, USA.
William J
WJ
Fulp
Ishikawa Prefectural Central Hospital, Kuratsukihigashi, Kanazawa, Japan.
Chiharu
C
Sugimori
Malignant Hematology Division, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
Jennifer
J
Paleveda-Pena
Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.
Jaroslaw P
JP
Maciejewski
Malignant Hematology Division, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
Alan F
AF
List
Immunology Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA Pearlie.Burnette@moffitt.org.
Pearlie K
PK
Epling-Burnette
D000328:Adult; D000368:Aged; D000818:Animals; D000961:Antilymphocyte Serum / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D011379:Prognosis; D011817:Rabbits; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
D000961:Antilymphocyte Serum; D007155:Immunologic Factors