ONCAlert | Upfront Therapy for mRCC

Case 2: Newly Diagnosed CLL; Del(17p)

Targeted Oncology
Published Online:1:43 PM, Tue February 4, 2020


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Anthony Mato, MD, MSCE: Speaking of adverse prognostic factors, it would be interesting if we can delve into another case. Sameer, you have a case of a patient with a deletion 17p, correct?

Sameer A. Parikh, MBBS: Yes. This is a 67-year-old man who reports increasing fatigue on routine checkup. At the time of diagnosis he undergoes a peripheral blood-flow cytometry, which shows a monoclonal population of B cells that express CD5, CD19, and CD23, as we discuss is typical for CLL [chronic lymphocytic leukemia]. FISH [fluorescence in situ hybridization] profile showed deletion 17p, and the remainder of the molecular analysis showed an unmutated IGVH gene profile, and TP53 mutation status. Would you like to talk about the TP53 mutation testing that is done through next-generation sequencing?

Nupam A. Patel, MD: As we mentioned before in the previous case, TP53 mutation sequencing is pretty standard across the board as 1 of the most important prognostic markers. Usually it follows with the deletion 17p. In about 90% of cases, if you have the deletion of 17p by FISH, you will have the TP53 mutation found on the other allele conferring a poorer prognosis.

Sameer A. Parikh, MBBS: Is there a recommendation to test for TP53 in the absence of deletion 17p by FISH? In what proportion of patients would we see a TP53 mutation, even though there is no deletion 17p by FISH?

Nupam A. Patel, MD: From a pathology perspective we usually get both those orders at the same time regardless. It’s not really that we get the FISH and then we kind of go with the sequencing after that. But usually, as I said before, if the deletion by FISH is there, you will find in 90% of the time that the mutation is also present on the other allele.

Sameer A. Parikh, MBBS: On physical exam this patient had cervical lymphadenopathy measuring at approximately 3 cm. The spleen was palpable, about 4 cm below the left costal margin. On laboratory studies the patient had a high white blood cell count of 151,000 with 71% lymphocytes. The hemoglobin was low at 9.3 g/dL. The platelet count was 126 mm3. The LDH [lactate dehydrogenase] was minimally elevated, and the serum beta-2-microglobulin was elevated at 4.1.

Anthony Mato, MD, MSCE: Before we go on, though, is this routine practice for everybody? Getting all the particular prognostic markers—beta-2s, LDHs—is that mandated?

Sameer A. Parikh, MBBS: We would typically get a beta-2-microglobulin and an LDH on all patients. These are prognostic markers that help us predict how the patients are going to do, but they’re not really predictive in that they don’t help me choose a particular treatment over another, unlike TP53-mutation status or the IGVH-mutation status.

Anthony Mato, MD, MSCE: It’s part of our routine panel as well.

Sameer A. Parikh, MBBS: I think some of the questions we’ve discussed for this patient—who, just to summarize, was a 67-year-old man who has a new diagnosis of CLL. It has many unfavorable characteristics in the CLL clone, unfortunately, that shows deletion 17p unmutated IGVH genes and TP53 mutation. What is the overall sort of prognosis on this patient, and how would you approach treatment?

Anthony Mato, MD, MSCE: If this patient were to read a textbook, I think we would say that this patient has an overall “poor prognosis.” I personally think it’s important to take the prognostic evaluation into the context of where the patient is in the course of their therapy. If this patient were newly diagnosed and without any disease-related symptoms, having a TP53 abnormality has different meaning to me than if its in the context of choosing a therapy. We touched on this earlier. I think the prognostic models are helpful in the context of what therapy you’re thinking about.

If this were 2012 and we were sitting here debating choice of FCR [fludarabine, cyclophosphamide, rituximab] or bendamustine for this patient, we would say this patient has a poor prognosis because they’re not likely to have a complete remission. It’s likely to have a short duration. Their survival is likely to be impacted by the fact that next therapies wouldn’t work. The same is probably true to a much lesser extent in 2020, where we have targeted agents that have demonstrated over and over again to at least partially overcome poor prognostic features of the disease, like a TP53 abnormality, maybe not completely. But 1 of the things we’ll probably touch upon as we talk about selection of therapy is that most of our modern therapies haven’t really been tested in a frontline in patients with poor prognostic features. So would anyone call this patient favorable in 2020 at this point? You know, even in the setting of having ibrutinib, or acalabrutinib, or venetoclax?

Shuo Ma, MD, PhD: I would not soon call it favorable.    

Anthony Mato, MD, MSCE: I agree.

Shuo Ma, MD, PhD: Even with the novel therapy, even though…we know that 17p deletion patients do terribly with a conventional immunochemotherapy. They do much better with the novel therapies. If you look at a novel therapy data, for example, with ibrutinib the 17p deletion patient still has a shorter progression-free survival. The median, I think, is about 27 months for a patient with 17p deletion CLL, whereas it’s much longer for the other patient group.

Anthony Mato, MD, MSCE: Do we have to have a little footnote that there’s almost a complete data gap in the frontline setting? It’s very hard to quote data...

Shuo Ma, MD, PhD: Correct...so that 19, 27 months was for relapsed setting. You’re correct.

Anthony Mato, MD, MSCE: Yeah, thanks.

Sameer A. Parikh, MBBS: There is a very small study, but that’s the longest follow-up that’s available from the NIH [National Institutes of Health], where they have, I believe, about 31 patients that have had a 5-year progression-free survival of approximately 80% in all patients who had deletion 17p, which are the best data that we have for a long-term follow-up in the frontline deletion 17p setting. It’s interesting to note that in addition to ibrutinib now, there are other treatment options available for patients with deletion 17p for frontline CLL.

Transcript edited for clarity.


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Anthony Mato, MD, MSCE: Speaking of adverse prognostic factors, it would be interesting if we can delve into another case. Sameer, you have a case of a patient with a deletion 17p, correct?

Sameer A. Parikh, MBBS: Yes. This is a 67-year-old man who reports increasing fatigue on routine checkup. At the time of diagnosis he undergoes a peripheral blood-flow cytometry, which shows a monoclonal population of B cells that express CD5, CD19, and CD23, as we discuss is typical for CLL [chronic lymphocytic leukemia]. FISH [fluorescence in situ hybridization] profile showed deletion 17p, and the remainder of the molecular analysis showed an unmutated IGVH gene profile, and TP53 mutation status. Would you like to talk about the TP53 mutation testing that is done through next-generation sequencing?

Nupam A. Patel, MD: As we mentioned before in the previous case, TP53 mutation sequencing is pretty standard across the board as 1 of the most important prognostic markers. Usually it follows with the deletion 17p. In about 90% of cases, if you have the deletion of 17p by FISH, you will have the TP53 mutation found on the other allele conferring a poorer prognosis.

Sameer A. Parikh, MBBS: Is there a recommendation to test for TP53 in the absence of deletion 17p by FISH? In what proportion of patients would we see a TP53 mutation, even though there is no deletion 17p by FISH?

Nupam A. Patel, MD: From a pathology perspective we usually get both those orders at the same time regardless. It’s not really that we get the FISH and then we kind of go with the sequencing after that. But usually, as I said before, if the deletion by FISH is there, you will find in 90% of the time that the mutation is also present on the other allele.

Sameer A. Parikh, MBBS: On physical exam this patient had cervical lymphadenopathy measuring at approximately 3 cm. The spleen was palpable, about 4 cm below the left costal margin. On laboratory studies the patient had a high white blood cell count of 151,000 with 71% lymphocytes. The hemoglobin was low at 9.3 g/dL. The platelet count was 126 mm3. The LDH [lactate dehydrogenase] was minimally elevated, and the serum beta-2-microglobulin was elevated at 4.1.

Anthony Mato, MD, MSCE: Before we go on, though, is this routine practice for everybody? Getting all the particular prognostic markers—beta-2s, LDHs—is that mandated?

Sameer A. Parikh, MBBS: We would typically get a beta-2-microglobulin and an LDH on all patients. These are prognostic markers that help us predict how the patients are going to do, but they’re not really predictive in that they don’t help me choose a particular treatment over another, unlike TP53-mutation status or the IGVH-mutation status.

Anthony Mato, MD, MSCE: It’s part of our routine panel as well.

Sameer A. Parikh, MBBS: I think some of the questions we’ve discussed for this patient—who, just to summarize, was a 67-year-old man who has a new diagnosis of CLL. It has many unfavorable characteristics in the CLL clone, unfortunately, that shows deletion 17p unmutated IGVH genes and TP53 mutation. What is the overall sort of prognosis on this patient, and how would you approach treatment?

Anthony Mato, MD, MSCE: If this patient were to read a textbook, I think we would say that this patient has an overall “poor prognosis.” I personally think it’s important to take the prognostic evaluation into the context of where the patient is in the course of their therapy. If this patient were newly diagnosed and without any disease-related symptoms, having a TP53 abnormality has different meaning to me than if its in the context of choosing a therapy. We touched on this earlier. I think the prognostic models are helpful in the context of what therapy you’re thinking about.

If this were 2012 and we were sitting here debating choice of FCR [fludarabine, cyclophosphamide, rituximab] or bendamustine for this patient, we would say this patient has a poor prognosis because they’re not likely to have a complete remission. It’s likely to have a short duration. Their survival is likely to be impacted by the fact that next therapies wouldn’t work. The same is probably true to a much lesser extent in 2020, where we have targeted agents that have demonstrated over and over again to at least partially overcome poor prognostic features of the disease, like a TP53 abnormality, maybe not completely. But 1 of the things we’ll probably touch upon as we talk about selection of therapy is that most of our modern therapies haven’t really been tested in a frontline in patients with poor prognostic features. So would anyone call this patient favorable in 2020 at this point? You know, even in the setting of having ibrutinib, or acalabrutinib, or venetoclax?

Shuo Ma, MD, PhD: I would not soon call it favorable.    

Anthony Mato, MD, MSCE: I agree.

Shuo Ma, MD, PhD: Even with the novel therapy, even though…we know that 17p deletion patients do terribly with a conventional immunochemotherapy. They do much better with the novel therapies. If you look at a novel therapy data, for example, with ibrutinib the 17p deletion patient still has a shorter progression-free survival. The median, I think, is about 27 months for a patient with 17p deletion CLL, whereas it’s much longer for the other patient group.

Anthony Mato, MD, MSCE: Do we have to have a little footnote that there’s almost a complete data gap in the frontline setting? It’s very hard to quote data...

Shuo Ma, MD, PhD: Correct...so that 19, 27 months was for relapsed setting. You’re correct.

Anthony Mato, MD, MSCE: Yeah, thanks.

Sameer A. Parikh, MBBS: There is a very small study, but that’s the longest follow-up that’s available from the NIH [National Institutes of Health], where they have, I believe, about 31 patients that have had a 5-year progression-free survival of approximately 80% in all patients who had deletion 17p, which are the best data that we have for a long-term follow-up in the frontline deletion 17p setting. It’s interesting to note that in addition to ibrutinib now, there are other treatment options available for patients with deletion 17p for frontline CLL.

Transcript edited for clarity.
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