Dr. Deborah M. Stephens from the Huntsman Cancer Institute recently presented at the 39th Annual Chemotherapy Foundation Symposium Innovative Cancer Therapy for Tomorrow (CFS). The presentation surrounded how critical identifying prognostic markers are for chronic lymphocytic leukemia (CLL). These markers can inform prognosis and what therapy is best for which individual patient. Additionally, these markers may be helpful for enrolling patients in the proper clinical trial.
CLL
CLL presents in many different ways. There are three primary prognostic factors. These are immunoglobulin variable heavy chain (IGHV), TP53, and fluorescence in situ hybridization (FISH). These factors can demonstrate how aggressive a patient’s disease is and whether or not it should be treated with the standard chemotherapy treatment or whether a targeted therapy would be more advantageous for the patient.
Further, these markers can explain when treatment should be started. Many patients need treatment immediately. Others can wait and be monitored.
Molecular risk and clinical risk should both be assessed before decisions are made.
Below is a summary of Dr. Stephens’ take on each of the markers mentioned above.
IGHV
If the gene has a minimum of 98% homology, then we know that IGHV is unmutated. After you learn whether IGHV is mutated or unmutated, you never have to check ever again. It doesn’t change as time goes by. If IGHV is unmutated, it will always be unmutated.
Dr. Stephens explains that she has an incredibly strong preference for treating patients who have unmutated IGHV with targeted therapy. About half of all patients have unmutated IGHV. These patients typically survive 9 years. Those with mutated IGHV typically live 25.
Ibrutinib-based therapy is much more advantageous than chemoimmunotherapy for patients with unmutated IGHV (90.7% compared to 62.5%).
IGHV status should be used to assess whether targeted agents should be used and how frequently patients need to be monitored.
FISH
FISH testing is a common tool to find CLL mutations such as deletion 11q, trisomy 12, deletion 17pm, and deletion 13q. Deletion 17p often has the worst outcomes. This patient subset has better outcomes with ibrutinib monotherapy than chemoimmunotherapy.
Deletion 11q also often has negative outcomes. However, research has shown that ibrutinib has been able to prolong progression-free survival (PFS) for this subset of patients. When treated with ibrutinib, deletion 11q patients are not considered at any higher risk than other patients.
Importantly, FISH may change as time goes on. Therefore, it should be frequently tested, especially before each round of therapy is administered.
TP53
TP53 aberrations are frequently linked with deletion 17p. 10% of CLL patients have TP53 aberrations.
It’s been shown that these individuals have improved outcomes with ibrutinib and venetoclax/obinutuzumab.
Why It’s Important
The CLL International Prognostic Index works to combine both molecular risk factors such as those discussed above and clinical risk factors which include Rai stage and age. Together, these will tell physicians whether their patient is at low risk or high risk of disease.
With this knowledge, the proper treatment plan can be created and the proper prognosis can be assessed.
You can read more about this means of assessment here.
