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ONCAlert | ESMO 2018 Congress

Case 2: 17p-Deleted CLL Progressing on Ibrutinib Therapy

Targeted Oncology
Published Online:9:14 AM, Tue May 1, 2018

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

William Wierda, MD, PhD: Welcome back to our program. Now we’re going to go to case No. 2. Dr. Jain?

Nitin Jain, MD: Case 2 is a 62-year-old gentleman who was diagnosed with CLL 6 years ago and was noted to have increased fatigue on routine follow-up. He has now been on ibrutinib for 4 years and has achieved a stable partial remission. Of note, at the time of original diagnosis, the flow cytometry showed a monoclonal B-cell population that was positive for CD5, CD19, and CD23. The FISH results show presence of deletion 17p. A molecular analysis showed that the patient is IGVH mutated, and the TP53 was wild-type. On physical examination, the patient currently has cervical lymphadenopathy, approximately 4 cm. His spleen is palpable; 5 cm below the costal margin. The white blood cell count is currently 153,000, with 73% lymphocytes. The patient is anemic, with a hemoglobin of 9.1. His platelet count is 125, his LDH is 250, and his beta2 microglobulin is 4.2.

So, looking at this case, a patient who has been ibrutinib for 4 years, it now appears that this patient may be progressing. Dr. Bagg, what other additional testing would you recommend at this time? And what comments do you have about the pathology in the initial diagnostic workup for this patient?

Adam Bagg, MD: As is standard practice, in the workup of a patient with chronic lymphocytic leukemia, it’s important, obviously, to confirm the classical immunophenotype of co-expression of CD5 and CD23 in monoclonal B cells, which was what was noted at diagnosis. At the time of presentation, a FISH panel will typically look at 5 or 6 different abnormalities. Trisomy 12, 13q14 deletion, deletion 11q22.3, and 11p deletions are found in most panels. Some other panels look at the 6q abnormalities or immunoglobulin translocations. In this particular patient, only deletion 17p was found, which is, as you know, a poor prognosticator. With regard to the immunoglobulin heavy-chain gene variable region, for somatic hypermutation analysis, in this patient, it was hypermutated. That, of course, is a good prognosticator, indicating a CLL cell that has transited through the germinal center.

The mutational panel that’s looked at in patients with CLL can contain a handful of genes, including TP53. A number of other genes may also be looked at, although I think it’s accepted that the most important one is TP53. Others that could be looked at, that may be relevant to a prognosis, are things like NOTCH1, SF3B1, XPO1, and so on and so forth.

Interestingly, in most patients who have deletion 17p, greater than 90% who have the FISH-detected deletion of the TP53 gene are accompanied by a TP53 mutation. This is a little bit unusual, to find the deletion without the mutation on the other allele. So, this seems like a straightforward diagnosis of chronic lymphocytic leukemia with some good prognostic things, like mutated IgH, and some bad prognostic things, like deletion 17p. Of note, this was only performed at the time of diagnosis. It is now 6 years later. Even though the diagnosis was well established 6 years ago, and it may not be necessary to confirm the diagnosis, some of these assays should be repeated. I think FISH should be repeated. The mutational analysis should also be repeated. It is probably not necessary to repeat the immunoglobulin heavy-chain mutation analysis. That usually remains stable. But I think the patient would benefit from repeat FISH analysis and repeat mutational testing.

William Wierda, MD, PhD: TP53 mutation analysis, in particular.

Adam Bagg, MD: But depending on the nature of your practice, the other genes could be looked at as well.

Matthew S. Davids, MD, MMSc: How commonly do you see mutated IGHV with deletion 17p? It seems like it is less common….

Adam Bagg, MD: I think it is unusual. As you know, most bad things go together with other bad things. So, this sort of discordance is unusual, but it happens.

Nitin Jain, MD: This patient, who has been on ibrutinib for 4 years, which was the appropriate frontline treatment because the patient has deletion 17p, has relapsed. Are there mutations, such as BTK mutations and other mutations, that we haven’t described, which may be evaluated for in this particular patient?

Adam Bagg, MD: Absolutely. If the assumption is that this patient has become resistant to therapy—in particular, BTK inhibition therapy— the leading causes are mutations, not only in the BTK gene preventing the drug from binding to the kinase but also mutations downstream of BTK that may make the BTK inhibition redundant. So, in a patient like this, it’s appropriate to look for mutations of not only BTK, but of phospholipase C-gamma 2.

Transcript edited for clarity.
 

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

William Wierda, MD, PhD: Welcome back to our program. Now we’re going to go to case No. 2. Dr. Jain?

Nitin Jain, MD: Case 2 is a 62-year-old gentleman who was diagnosed with CLL 6 years ago and was noted to have increased fatigue on routine follow-up. He has now been on ibrutinib for 4 years and has achieved a stable partial remission. Of note, at the time of original diagnosis, the flow cytometry showed a monoclonal B-cell population that was positive for CD5, CD19, and CD23. The FISH results show presence of deletion 17p. A molecular analysis showed that the patient is IGVH mutated, and the TP53 was wild-type. On physical examination, the patient currently has cervical lymphadenopathy, approximately 4 cm. His spleen is palpable; 5 cm below the costal margin. The white blood cell count is currently 153,000, with 73% lymphocytes. The patient is anemic, with a hemoglobin of 9.1. His platelet count is 125, his LDH is 250, and his beta2 microglobulin is 4.2.

So, looking at this case, a patient who has been ibrutinib for 4 years, it now appears that this patient may be progressing. Dr. Bagg, what other additional testing would you recommend at this time? And what comments do you have about the pathology in the initial diagnostic workup for this patient?

Adam Bagg, MD: As is standard practice, in the workup of a patient with chronic lymphocytic leukemia, it’s important, obviously, to confirm the classical immunophenotype of co-expression of CD5 and CD23 in monoclonal B cells, which was what was noted at diagnosis. At the time of presentation, a FISH panel will typically look at 5 or 6 different abnormalities. Trisomy 12, 13q14 deletion, deletion 11q22.3, and 11p deletions are found in most panels. Some other panels look at the 6q abnormalities or immunoglobulin translocations. In this particular patient, only deletion 17p was found, which is, as you know, a poor prognosticator. With regard to the immunoglobulin heavy-chain gene variable region, for somatic hypermutation analysis, in this patient, it was hypermutated. That, of course, is a good prognosticator, indicating a CLL cell that has transited through the germinal center.

The mutational panel that’s looked at in patients with CLL can contain a handful of genes, including TP53. A number of other genes may also be looked at, although I think it’s accepted that the most important one is TP53. Others that could be looked at, that may be relevant to a prognosis, are things like NOTCH1, SF3B1, XPO1, and so on and so forth.

Interestingly, in most patients who have deletion 17p, greater than 90% who have the FISH-detected deletion of the TP53 gene are accompanied by a TP53 mutation. This is a little bit unusual, to find the deletion without the mutation on the other allele. So, this seems like a straightforward diagnosis of chronic lymphocytic leukemia with some good prognostic things, like mutated IgH, and some bad prognostic things, like deletion 17p. Of note, this was only performed at the time of diagnosis. It is now 6 years later. Even though the diagnosis was well established 6 years ago, and it may not be necessary to confirm the diagnosis, some of these assays should be repeated. I think FISH should be repeated. The mutational analysis should also be repeated. It is probably not necessary to repeat the immunoglobulin heavy-chain mutation analysis. That usually remains stable. But I think the patient would benefit from repeat FISH analysis and repeat mutational testing.

William Wierda, MD, PhD: TP53 mutation analysis, in particular.

Adam Bagg, MD: But depending on the nature of your practice, the other genes could be looked at as well.

Matthew S. Davids, MD, MMSc: How commonly do you see mutated IGHV with deletion 17p? It seems like it is less common….

Adam Bagg, MD: I think it is unusual. As you know, most bad things go together with other bad things. So, this sort of discordance is unusual, but it happens.

Nitin Jain, MD: This patient, who has been on ibrutinib for 4 years, which was the appropriate frontline treatment because the patient has deletion 17p, has relapsed. Are there mutations, such as BTK mutations and other mutations, that we haven’t described, which may be evaluated for in this particular patient?

Adam Bagg, MD: Absolutely. If the assumption is that this patient has become resistant to therapy—in particular, BTK inhibition therapy— the leading causes are mutations, not only in the BTK gene preventing the drug from binding to the kinase but also mutations downstream of BTK that may make the BTK inhibition redundant. So, in a patient like this, it’s appropriate to look for mutations of not only BTK, but of phospholipase C-gamma 2.

Transcript edited for clarity.
 
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