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TP53 and Deletion 17p as Prognostic Factors in CLL

Insights From: Michael Choi, MD, UC San Diego Medical Center; Matthew S. Davids, MD, Dana-Farber Cancer Institute; William Wierda, MD, PhD, MD Anderson Cancer Center
Published: Saturday, Mar 31, 2018



Transcript: 

William Wierda, MD, PhD: We’ve done quite a bit of work with prognostic factors in CLL and looked at predictive markers for time-to-first-treatment, predictive markers for how patients do with treatments, predictive markers for duration of remission, and predictive and prognostic factors for overall survival. It is a complicated area. It’s changing. It’s changing because of the treatments that we have, the new treatments that have become available over the past 5 years.

Generally, regarding the high-risk prognostic factors that we’ve identified with chemoimmunotherapy, the main one that remains a high-risk feature with new treatments is this presence of 17P deletion or deletion of the TP53 gene. Many of the patients who are missing TP53 by virtue of having the 17P deletion also have mutation in the TP53 gene on the other allele. There is a double knockout of the TP53 gene in the leukemia cells that renders them refractory or resistant to treatment with chemoimmunotherapy. So, 17P deletion is a very high-risk feature in CLL, particularly in chemoimmunotherapy treatments, because those patients do not respond to treatment. If they do get a response, it’s very transient and they get all the toxicities associated with chemoimmunotherapy. We avoid chemoimmunotherapy for patients with a 17P deletion or mutation in TP53.

Most of the assessment for prognostic factors includes FISH testing, which will give you information about 17P deletion. What hasn’t routinely been used in the community has been the sequencing of TP53 or the Digene TP53 test, so I think that’s an important topic and it’s important for people to understand that there are 2 tests. There’s the FISH test and there’s sequencing for TP53. Both of them are important and we should be checking both of those for our patients, particularly if we’re thinking about chemoimmunotherapy as an option.

The 17p deletion, as I mentioned, has a high risk associated with it for patients getting chemoimmunotherapy. It’s also a higher risk feature for patients getting the small molecule inhibitors: for example, ibrutinib. We know for relapsed patients who receive ibrutinib, there is shorter progression-free survival for those patients who have a 17p deletion and also for patients who have a complex karyotype. Although they do exceptionally well, compared with what we used to be able to do with chemotherapy if they get ibrutinib, they’re still at a higher risk. The median progression-free survival for relapsed patients with 17p deletion receiving ibrutinib therapy is about 32 months.

With chemoimmunotherapy, it’s much shorter, but I think that illustrates an important feature.  We have to have an understanding and knowledge of that particular feature not only to choose the treatment by avoiding chemoimmunotherapy, but also to have an understanding that they may have a shorter progression-free survival if they get the small molecule inhibitors such as ibrutinib. So, among the prognostic factors that we’ve talked about over many years, 17p deletion and mutated TP53 are still very important across treatments. They are prognostic across treatment types.

Transcript Edited for Clarity 
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Transcript: 

William Wierda, MD, PhD: We’ve done quite a bit of work with prognostic factors in CLL and looked at predictive markers for time-to-first-treatment, predictive markers for how patients do with treatments, predictive markers for duration of remission, and predictive and prognostic factors for overall survival. It is a complicated area. It’s changing. It’s changing because of the treatments that we have, the new treatments that have become available over the past 5 years.

Generally, regarding the high-risk prognostic factors that we’ve identified with chemoimmunotherapy, the main one that remains a high-risk feature with new treatments is this presence of 17P deletion or deletion of the TP53 gene. Many of the patients who are missing TP53 by virtue of having the 17P deletion also have mutation in the TP53 gene on the other allele. There is a double knockout of the TP53 gene in the leukemia cells that renders them refractory or resistant to treatment with chemoimmunotherapy. So, 17P deletion is a very high-risk feature in CLL, particularly in chemoimmunotherapy treatments, because those patients do not respond to treatment. If they do get a response, it’s very transient and they get all the toxicities associated with chemoimmunotherapy. We avoid chemoimmunotherapy for patients with a 17P deletion or mutation in TP53.

Most of the assessment for prognostic factors includes FISH testing, which will give you information about 17P deletion. What hasn’t routinely been used in the community has been the sequencing of TP53 or the Digene TP53 test, so I think that’s an important topic and it’s important for people to understand that there are 2 tests. There’s the FISH test and there’s sequencing for TP53. Both of them are important and we should be checking both of those for our patients, particularly if we’re thinking about chemoimmunotherapy as an option.

The 17p deletion, as I mentioned, has a high risk associated with it for patients getting chemoimmunotherapy. It’s also a higher risk feature for patients getting the small molecule inhibitors: for example, ibrutinib. We know for relapsed patients who receive ibrutinib, there is shorter progression-free survival for those patients who have a 17p deletion and also for patients who have a complex karyotype. Although they do exceptionally well, compared with what we used to be able to do with chemotherapy if they get ibrutinib, they’re still at a higher risk. The median progression-free survival for relapsed patients with 17p deletion receiving ibrutinib therapy is about 32 months.

With chemoimmunotherapy, it’s much shorter, but I think that illustrates an important feature.  We have to have an understanding and knowledge of that particular feature not only to choose the treatment by avoiding chemoimmunotherapy, but also to have an understanding that they may have a shorter progression-free survival if they get the small molecule inhibitors such as ibrutinib. So, among the prognostic factors that we’ve talked about over many years, 17p deletion and mutated TP53 are still very important across treatments. They are prognostic across treatment types.

Transcript Edited for Clarity 
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