Submitted July 8, 2008
Accepted October 22, 2008
Of mice and men: an open label pilot study for treatment of immune thrombocytopenic purpura (ITP) by an inhibitor of Syk
Anna Podolanczuk*, Alan H Lazarus, Andrew R Crow, Elliot Grossbard, and James B. Bussel
Department of Medicine, New York Presbyterian Hospital, Columbia University Medical Center, New York, NY, United States
Canadian Blood Services & the Li Ka Shing Institute of St. Michael's Hospital, Toronto, Canada
Rigel Pharmaceuticals, South San Francisco, CA, United States
Departments of Pediatrics and Medicine, New York Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, United States
* Corresponding author; email: ajp2158{at}columbia.edu.
To determine if inhibition of Syk would be useful in Fc
R-dependent cytopenias such as immune thrombocytopenic purpura (ITP) or autoimmune hemolytic anemia (AHA), mouse models were employed to evaluate efficacy of R406, an inhibitor of Syk function, in treating cytopenia. Both disease models responded favorably to treatment, with amelioration of ITP being more dramatic of the two. Thus, Phase II clinical trial was initiated to study the effects of Syk inhibition in humans with ITP. Sixteen adults with chronic ITP were entered into an open label, single arm, cohort, dose escalation trial beginning with 75mg and escalating as high as 175mg twice daily. Doses were increased until either a persistent response was seen, toxicity occurred, or 175mg twice daily was reached. Eight patients achieved persistent responses with counts >50K on >67% (actually 95%) of their study visits, including three who had not persistently responded to thrombopoietic agents. Four others had non-sustained responses. The mean peak platelet count was >100,000/mm3 in these 12 patients. Toxicity was primarily GI-related with diarrhea (urgency) and vomiting; 2 patients had transaminitis. In conclusion, inhibition of Syk was an efficacious means of increasing and maintaining the platelet count in half the patients with chronic refractory ITP. This trial is registered with ClinicalTrials.gov under Identifier NCT00706342.
