During the summer months, many of my patients go fishing. I encourage my CLL patients to gain an appreciation of a different type of fishing. FISH testing provides a vast amount of information that is useful in predicting disease progression and that aids in the selection of appropriate treatments. FISH results can seem like just a sea of numbers. My goal is to help patients understand FISH results, and I hope the description below will be useful for you.
17p deletion: The Whale’s Tale
Many of you hear “Chromosome 17p deletion” and immediately assume it is “bad, bad, bad”. In actuality, this is partially right and partially wrong. Research from Professor Daniel Catovsky first indicated that the presence of 17p deletion might not be all bad news. A British clinical trial showed that patients with less than 20% of the cells having 17p del, experienced a more favorable treatment outcome than those with a higher percentage of abnormal cells.
Consequently, other investigators have evaluated the outcome of patients who had 17p del at time of diagnosis. In Blood recently, Drs. Constantine Tam and Tait Shananfelt from MDACC and Mayo Clinic, evaluated the outlook for 99 patients with 17p deletion at initial diagnosis. Two thirds of these patients had no symptoms and only half required therapy over a three year follow-up period. The risk of requiring therapy was greatest in the first 18 months of follow-up. Rai stage and lack of mutation in the immunoglobulin heavy chain gene (IgVH) were also strong predictors of progression. Overall survival was 65% at three years. During follow-up, some patients actually lost the 17p abnormality on the repeat FISH test; usually these patients had a very low percentage of abnormal cells at initial diagnosis. Of those patients requiring treatment, 72% of patients responded to an FCR-like regimen (fludarabine, cyclophosphamide, rituximab) and 81% to FCR with the addition of alemtuzumab. While it is said that rituximab is not likely to work in patients with 17p deletion, 3 out of 6 patients did respond.
Patients have an increased likelihood of having abnormalities in chromosome 17 as their disease progresses and after various forms of therapy. At initial therapy, patients have a 5-10% likelihood of having a 17p del, but in relapsed populations the frequency goes up to 20 to 25%. Traditionally, the relapsed group with 17p del does not respond very well to additional treatments. However, there are increasing reports of agents such as alemtuzumab, flavopiridol and the combination of bendamustine and rituximab having activity in patients with 17p deletion.
The new monoclonal antibody ofatumumab (Arzerra) was also found to have a favorable response rate in fludarabine-refractory patients with 17 p deletion unless they had very bulky lymph node disease. New regimens are now being developed which have the potential to improve the complete response rate and response duration.
It is also important to mention that a number of patients that are 17p deleted will eventually require allogeneic stem cell transplantation and they may need to consider this as a therapeutic option. We are trying to improve the response duration with therapy so patients will have the time to get prepared for potential allogeneic stem cell transplantation. While based on a small number of patients, the data suggest that the 17p del group of patients do as well as others with stem cell transplantation.
Most patients with a large percentage of 17p deleted cells will have a mutation in the p53 gene, an important gene in predicting the effects of chemotherapy and radiation. Some patients who do not have 17p loss using FISH analysis will have a mutation in the p53 gene. These patients have a prognosis very similar to the 17p deleted group of patients, as reported by Dr. Thorsten Zenz and colleagues from Germany.
Patients should be informed that 17p del is an important finding on FISH analysis; doctors should be encouraged to conduct this test on all patients at initial diagnosis. However, the “doom and gloom” which surrounds 17p is not entirely warranted. A finding of 17p deletion on fish analysis warns the doctor that he or she should watch very closely for progression of disease and consider referral to a specialist center. Doctors should explain that while some patients with 17 p deletion do quite well on different treatments, the risk of failure with any treatment is higher. In particular, the likelihood of achieving a complete remission is significantly lower with the loss of chromosome 17. As more information is generated, the usefulness of FISH as a prognostic marker will increase and we should be in a better position to design more rational treatments.
What happens when 11q is in the tackle box?
Patients with 11q abnormalities tend to have steadily progressive disease and the majority may require therapy within one to two years of diagnosis when there is clear evidence of CLL progression or development of symptoms. Almost all of the 11q deleted patients have an unmutated IgVH gene. This is the only FISH type that is strongly correlated with mutation status.
Initially, it was noted that cyclophosphamide combined with fludarabine significantly improved the likelihood of responding if you have an 11q abnormality. The good news is that the addition of rituximab to create the FCR regimen produces a very high complete remission rate (70 to 75%) when patients with 11q abnormalities need treatment. However, patients with 11q deletion will usually have disease recurrence after three to five years. There is growing consensus that patients in remission should receive consolidatation treatment in order to sustain the remission, but there is no specific data to recommend a particular approach.
In addition, a number of patients will only develop 11q abnormalities under the influence of treatment. FISH testing is important at diagnosis and recurrence to see if there has been evolution of abnormalities in chromosomes 11. A number of important genes are lost in the area of chromosome 11, including the ATM gene. Many of these genes are involved with repair of DNA damage. Clinical trials of FCR-like regimens are producing prognostic information which will assist us in determining timing of interventions, success of salvage programs, and eventual benefit of stem cell transplantation.
What is the catch with trisomy 12?
Patients with no abnormality on regular chromosome analysis can have an additional chromosome 12 by FISH techniques. This is called trisomy 12. Most CLL patients have cells which are very similar: small lymphocytes with consistency in size and shape. However patients with chromosome 12 abnormalities (trisomy 12) have cells that appear to be more active, larger and irregular in shape, raising suspicion that disease is more aggressive. The response to treatment in trisomy 12 patients is very good with a high likelihood of remission duration of greater than 5 years. We know now that patients with trisomy 12 have the highest number of CD20 molecules on the surface of their cells (CD20 is the target for monoclonal antibodies, rituximab and ofatumumab). Patients with trisomy 12 appear to have a very stable genetic pattern and tend to not develop abnormalities in chromosome 11 or 17 under the influence of treatment.
Hooked on FISH
We are finding that every CLL patient is unique. Classifying them only by age and stage is inadequate. The mutation status tells us much about the likelihood of genetic stability, progression of disease, need for treatment, response to treatment, and length of a remission. The FISH tests also give us tremendous amounts of information pre- and post-treatment. All of these parameters are integrated into the decision-making process as to when to initiate treatment, the selection of the optimal regimen, the use of a consolidation regimen after initial treatment and the timing of an eventual transplant.
Patients should encourage their doctor to get the FISH tests when they first present, at the start of initial treatment, and at the time of relapse. It is not a good test for monitoring for residual disease. The mutation status needs only to be done once because it is a constant throughout the lifetime of the CLL patient. The ZAP-70 test is still not reproducible from one lab to another and CD38 expression is not as strong as other prognostic characteristics. All in all, our precision in defining the clinical behavior of any particular patient is improving at a very rapid rate. I am confident we will be able to select the appropriate treatments with curative potential for most patients with CLL in the next few years.