ASH 2012

 

Image obtained from www.hematology.org.

Before 2012 becomes a memory, we want to look back at the highlights of the 2012 ASH Annual Meeting. The American Society of Hematology meeting takes place each December. Researchers from around the world are invited to present their latest research on blood diseases and disorders. A copious amount of information and accomplishments were presented on CLL.

 

Trial results on the kinase inhibitor, ibrutinib, and CARs dominated the CLL scene. You can catch a glimpse of the excitement by watching the videos in the side bar to the left. Other topics were also discussed at ASH; they may not have received as much media attention but are important pieces in the quest to cure CLL.

 

Data was presented on several new treatments that target specific molecules. Multiple drugs are being tested that target bcl-2, an important molecule that prevents CLL cells from dying. ABT-199 is being tested in phase I trials, and ABT-263 has been compared to and combined with rituximab in a phase II trial. Both drugs are effective but come with side effects. ABT-263 appears to increase responses when combined with rituximab even in 17p- patients (generally an indicator of poor response to treatment).

 

Researchers from Sweden and Iran presented laboratory results on a monoclonal antibody which targets ROR1, a protein overexpressed on CLL cells but not found on normal B-cells. In the studies, the anti-ROR1 antibody deactivated signaling proteins involved in CLL cell survival and caused CLL cells to die. Based on information gathered, additional studies are needed to better understand signaling pathways associated with ROR1.

 

Signaling molecules are critical for CLL cells to communicate with other cells and to survive. Some of these molecules are the targets for the drugs mentioned above. However, there are hundreds of potential targets. Researchers continue to analyze all of the molecules and pathways they can find to fully grasp the complex interactions. There were several ASH presentations on new molecules and their potential role in CLL development. 

 

Some researchers are going beyond molecules and signals and into the depths of the genes that determine the makeup of the cell. Gene mutations are providing huge insight into the diversity of CLL.

 

NOTCH1 is a newly discovered gene in CLL cells which occurs in approximately 10% of patients. According to data from a study conducted in Germany, patients with a NOTCH1 mutation did not benefit from the addition of rituximab to the fludarabine and cyclophosphamide (FC) regimen. Surprisingly, a small portion of patients with the 13q- on FISH, which is the most favorable prognostic factor, had mutations of a new gene, SF3B1, which is associated with a poor outcome.    

 

These and other newly discovered genes will continue to be analyzed against established prognostic markers. The goal is to know how every patient's disease will respond to treatment and to more effectively decipher the most optimal treatment for each patient.

 

Ibrutinib Versus Ofatumumab

 

The buzz word these days is ibrutinib because of the dramatic results of Phase I and II clinical trials recently presented at ASH. It is being put up to a final test before being considered for approval by the FDA and international government agencies for the treatment of CLL.

 

CLL patients are currently enrolling in a Phase III clinical trial comparing ibrutinib to ofatumumab, a monoclonal antibody already approved for the treatment of CLL. The study, known as the RESONATE study, is open to patients who have relapsed or who have refractory CLL, including those with 17p- which is considered a poor prognostic marker.

 

Ibrutinib blocks the Bruton's tyrosine kinase (Btk) protein which is found on healthy B-cells and CLL cells. Btk functions normally in healthy B-cells, but not in CLL cells. It is part of a signaling pathway needed by CLL cells for growth and survival. Btk also helps keep CLL cells in the lymph nodes where they are better protected.

 

Blocking Btk liberates the CLL cells into the blood stream

   

Ofatumumab targets CD20 which is a molecule found on the surface of B-cells, including CLL cells. It was approved in 2010 for the treatment of CLL. Both ofatumumab and rituximab, another monoclonal antibody, target the CD20 molecule. Ofatumumab seems to be better at binding to CD20 than rituximab in CLL cells. It is also effective in patients who did not benefit from treatment with rituximab, making it a good comparator to ibrutinib. 

 

The primary goal of this Phase III trial is to see if there is a clinically significant improvement in progression-free survival when ibrutinib is compared to ofatumumab, an approved treatment option. It must be shown through trial results that ibrutinib is equally effective with fewer side effects or superior to standard therapy. These results will be used by the FDA when considering the approval of ibrutinib; FDA approval would make the treatment more widely available to CLL patients.    

 

The trial is currently open at more than 50 locations around the world and is accruing rapidly. It is a randomized trial which means the patient, the doctor and the drug company cannot choose which patient will go on which drug. To eliminate bias, a computer decides whether patients will go on the ibrutinib or ofatumumab arm. Randomized trials help demonstrate that a particular agent or regimen is beneficial on average to a large population of patients.

 

Additional ibrutinib trials are ongoing and others are planned. Ibrutinib has been beneficial for patients regardless of prognostic markers. One new study will specifically target patients with 17p- which are often difficult to treat. Other trials will combine ibrutinib with additional therapies for patients with relapsed or refractory CLL and there is also a trial planned comparing ibrutinib with chlorambucil as frontline therapy in elderly patients.

 

Phase III trial results will be reviewed by the FDA to make sure the treatment is safe and effective for use by all patients. If approved, ibrutinib will be available for CLL patients at doctors' offices worldwide. We will continue to provide updates on this Phase III trial and others as they become available.

 

Click here to read additional information about the trial from clinicaltrials.gov. 

 

As with any study, enrollment is limited and a patient must meet eligibility criteria. Consult with your physician to determine if a clinical trial is an appropriate avenue for treatment.

 

Sincerely,

CLL Global Research Foundation