Acute chest syndrome (ACS) is the leading cause of death for individuals with sickle cell disease (SCD). Current treatment for ACS is transfusion, which is complicated by alloimmunization, reactions, and infection. Additional therapies for ACS are desperately needed. The objective of this application is to determine the feasibility of conducting a clinical trial examining a novel agent, regadenoson, for the treatment of ACS in individuals with SCD. We have abundant preliminary data in murine models and patients with SCD to suggest that regadenoson, an adenosine2A receptor agonist, may interrupt ischemia/reperfusion injury (IRI) by targeting invariant NKT cells and decrease the severity of ACS episodes. We are currently performing a phase I dose finding and safety study of regadenoson in children and adults with SCD. Our ultimate goal is to extend the findings of the phase I study to the treatment of ACS. We plan to perform a multi-center, randomized phase IIb trial comparing regadenoson plus standard therapy versus standard therapy alone for ACS using length of stay as the primary outcome. We have assembled a consortium of seven institutions led by experienced SCD investigators to participate in this multi-center trial. This planning grant will be used to generate the data necessary to appropriately design the phase IIb study. In this application, we will: 1) determine whether sufficient numbers of patients with ACS can be accrued in our study consortium;and 2) measure the variance in length of stay among individuals with SCD and ACS who are receiving regadenoson. We will treat 20 participants with HbSS/HbS-thalassemia0, ages 14 to 70 years, who are admitted to the hospital for mild to moderate ACS episodes. Participants will receive a 48 hour infusion of a safe and biologically effective dose of regadenoson that will be added to standard therapy elected by the patients'physicians. We estimate that the incidence of ACS episodes in our consortium is 10 per month. Conservatively, we estimate that 1 patient will be enrolled for every 10 ACS episodes and over the 24 month funding period (enrolling about 1 patient per month) we will meet our accrual goal. Based on the data generated from this study, we plan to submit an R01 to support the phase IIb clinical trial. We anticipate that regadenoson may ultimately be used as an adjunct to transfusion therapy or may obviate the need for transfusion in some cases of ACS.

Public Health Relevance

Sickle cell disease is a genetic condition of the blood. Acute chest syndrome is the most lethal complication of sickle cell disease. We will conduct a study in people with sickle cel disease and acute chest syndrome in order to obtain preliminary information about a drug called regadenoson;the results of this study will be used to design a larger trial to determine if regadenoson is an effective therapy for acute chest syndrome. ! !

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Planning Grant (R34)
Project #
5R34HL108757-02
Application #
8313888
Study Section
Special Emphasis Panel (ZHL1-CSR-D (M2))
Program Officer
Luksenburg, Harvey
Project Start
2011-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$341,034
Indirect Cost
$94,564
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Field, Joshua J; Nathan, David G; Linden, Joel (2014) The role of adenosine signaling in sickle cell therapeutics. Hematol Oncol Clin North Am 28:287-99
Archer, Natasha M; Shmukler, Boris E; Andolfo, Immacolata et al. (2014) Hereditary xerocytosis revisited. Am J Hematol 89:1142-6