Note: This review is based upon a presentation at the 2012 American Society of Hematology (ASH) Annual Meeting, December 7-10 in Atlanta, Georgia.The full abstract may be reviewed on the ASH Annual Meeting Web site. Search by entering the title in the search box. The abstract number is referenced to access the full report.
Tommaso Rondelli, Antonio M. Risitano, Régis Peffault de Latour, Benedetta Peruzzi, Ricci Patrizia, Wilma Barcellini, Anna Paola Iori, Carla Boschetti, Veronica Valle, Veronique Frémeaux-Bacchi, Maria De Angioletti, Gerard Socie, Lucio Luzzatto, and Rosario Notaro
This study by a group of researchers from Italy examined inherited factors that influence how patients will respond to eculizumab. As way of background, some patients with PNH who go on Eculizumab have an increase in their hemoglobin up to the normal range and never require another transfusion. Other patients will have an increase in their hemoglobin and will be able to discontinue transfusions, but will still be anemic. Others will be anemic and will still require transfusions.
The usual explanation for why some patients do not respond well to eculizumab is that they actually are behaving more like patients with aplastic anemia than patients with PNH—and these patients will often respond well to treatments used for aplastic anemia. On the other hand, some patients will be “rapid metabolizers” of the eculizumab drug and will need a higher dose. However, in yet another group of patients, there is something called “extravascular hemolysis” which is keeping the hemoglobin from recovering fully. Here the red cells are still being broken down, just more slowly than before. The drug is helping, but not as much as would have been hoped. This is because eculizumab does not fully block all complement proteins.
This study excluded patients who really had aplastic anemia rather than PNH and focused on the third group of patients who still required transfusion. Researchers looked to see if there were genetic factors at play in the group that had “extravascular hemolysis”. In fact, there is a gene called, CR1, which controls complement proteins. There are different versions of this gene in different people, just like some people have genes for tallness and others have genes for shorter stature. 6 out of 72 patients with PNH happened to have inherited from both parents the rarer version of this CR1 gene. Interestingly, they had a higher chance of being in the group that still required transfusions. Those who did not have any copies of this version of the gene had the best chance of not needing transfusion.
A separate study by a group from Japan [Yamamoto, et al, 988 Crucial Role of Complement Receptor Type 1 On the Accumulation of Complement Component 3 On Erythrocytes in Patients with PNH Treated with Eculizumab] showed that the amount of CR1 on red cells varied between individuals. Those with the highest level of CR1 seemed to be most protected from the effects of Complement Component 3. This Japanese study suggests an explanation for the findings of the Italian group—the amount of CR1 on the surface of red cells may determine whether or not patients are protected against extravascular hemolysis, and the level of CR1 on the surface of the red cells may be determined by genetics. These studies suggest that as for many other medications, there are genetic factors that will determine how much benefit there will be with the medication.