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ONCAlert | Upfront Therapy for mRCC

Case 3: Progression on Ibrutinib Followed by Richter Transformation

Targeted Oncology
Published Online:12:34 PM, Thu May 10, 2018

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Matthew S. Davids, MD, MMSc: This patient actually has done quite well on ibrutinib for a couple of years now. Some issues have come up. We talked about some neutropenia, which was seen early on. This patient also had some grade 3 hypertension and some abnormal ECG results. We saw cardiology, and they were able to adjust the antihypertensive regimen. So, that was manageable.

Now we’re about 2 years into ibrutinib treatment. The patient is now 77 years old. They’ve described sudden weight loss, fatigue, and a rapidly growing left axillary lymph node. Certainly, it is very concerning, in a chronic disease (which is usually quite slow moving), to see anything happening suddenly. Rightfully so, this patient is referred for a PET/CT scan, which shows an axillary lymph node that has an SUV of 15—certainly very concerning and higher than what we might expect in a typical CLL case. At this point, a lymph node biopsy is done. This is consistent with a DLBCL histology. Dr. Bagg, may you comment on the pathology of this scenario?

Adam Bagg, MD: The avidity is suggestive of something that has gone awry, that has progressed. Histologically, this is reported to show a diffuse large B-cell lymphoma. It is usually, or ought to be, straightforward, to distinguish diffuse large B-cell lymphoma from chronic lymphocytic leukemia. But there are potential pathologic caveats that might mislead those who are less familiar with looking at CLL lymph nodes, since we usually diagnose the disease in peripheral blood or bone marrow. One feature that might be misinterpreted in chronic lymphocytic leukemia, even in the so-called chronic phase, is the disease histologically being characterized by pseudofollicular proliferation centers, which are collections of cells that don’t look like CLL cells. They’re collections of larger cells that resemble prolymphocytes but do not resemble large cells. To a pathologist who is not familiar with looking at CLL lymph nodes, those may be concerning for large cell transformation. They do not indicate large cell transformation. It is very important to be aware of their existence.

Things become a little bit concerning when you see enlarged proliferation centers. Historically, there was a lot of literature on the prognostic relevance of large proliferation centers. That sort of went out of vogue. More recently, there are data to suggest that large confluent proliferation centers are a poor prognosticator. And yet it is still not indicative of Richter transformation. So, it’s important to be aware of that. And, of course, in any phase of CLL, you will see a sprinkling of large cells. That’s fine and is almost expected in typical chronic lymphocytic leukemia, histologically. But when the cells form sheaths and sizable sheaths, only at that point should one be making a diagnosis of diffuse large B-cell lymphoma. It’s not always the case, but one assumes that large cell lymphoma reflects transformation of the underlying chronic lymphocytic leukemia.

I think the current thinking is that approximately 25% of diffuse large B-cell lymphomas that arise in the setting of chronic lymphocytic leukemia are actually clonally unrelated to the CLL itself. It’s important, when you encounter a diffuse large B-cell lymphoma in the setting of CLL, to do appropriate studies, if you are able to, to see whether they are clonally related. One could simply do that, with appropriate tools, by looking at the clonal immunoglobulin heavy-chain gene rearrangement to see whether they are similar or different. Understandably, that has some prognostic relevance with a de novo diffuse large B-cell lymphoma perhaps being less aggressive than one that is transformed from an underlying CLL. I’m not qualified to address whether that translates into a different therapeutic approach, but I think it’s important to know whether that is, in fact, the case—whether it is a true transformation or just a second clonally unrelated DLBCL.

Matthew S. Davids, MD, MMSc: Those are all very important points. Clearly, the pathology is key here. Dr. Wierda, this is a patient who has a very good clinical story for Richter syndrome. We see that the LDH is markedly elevated, and we see this PET/CT finding of an SUV of 15. Are there any new data that might inform us as to whether this could just be ibrutinib progression in CLL? Or is this a slam dunk for Richter, without the biopsy?

William Wierda, MD, PhD: Well, if a patient has a clinical presentation of Richter transformation, we really need to do a biopsy. We use PET/CT to help direct biopsy. Many times, in a patient who actually has Richter transformation, they’ll present with a nodal area that is rapidly enlarging. The clinical suspicion is there. Other things that lead to an increased suspicion for Richter transformation are elevated LDH, and patients usually look sick. They have fever and fatigue. So, we do the PET/CT. We’ve done an analysis on outcomes for patients who we suspect have Richter, who have had a PET/CT. We noted that the outcomes, whether or not we show that there’s Richter, are poor if there are active nodes.

We will typically biopsy patients who have an SUV of 10 or higher. In our analysis, the patients who had diagnosed Richter and who had an elevated SUV without a diagnosis of Richter did similarly poorly with salvage therapy. That said, I think it’s important to do a biopsy to clarify whether or not the patient has a Richter transformation. It’s also important to know whether or not it’s clonally related. We do know that the patients who have a clonally unrelated transformation do better, clinically, than patients who have a clonally related transformation.

Matthew S. Davids, MD, MMSc: I think that’s so important. The therapy will be different if it’s CLL versus Richter, even though the outcomes may still be poorer for the patients with CLL. So, that’s a really important point.

William Wierda, MD, PhD: We didn’t talk about it, but the other thing to note is that although it’s not technically referred to as Richter transformation, you can have a transformation event with a different histology—that’s Hodgkin histology, which is uncommon.

Matthew S. Davids, MD, MMSc: Right.

Transcript edited for clarity.
 

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Matthew S. Davids, MD, MMSc: This patient actually has done quite well on ibrutinib for a couple of years now. Some issues have come up. We talked about some neutropenia, which was seen early on. This patient also had some grade 3 hypertension and some abnormal ECG results. We saw cardiology, and they were able to adjust the antihypertensive regimen. So, that was manageable.

Now we’re about 2 years into ibrutinib treatment. The patient is now 77 years old. They’ve described sudden weight loss, fatigue, and a rapidly growing left axillary lymph node. Certainly, it is very concerning, in a chronic disease (which is usually quite slow moving), to see anything happening suddenly. Rightfully so, this patient is referred for a PET/CT scan, which shows an axillary lymph node that has an SUV of 15—certainly very concerning and higher than what we might expect in a typical CLL case. At this point, a lymph node biopsy is done. This is consistent with a DLBCL histology. Dr. Bagg, may you comment on the pathology of this scenario?

Adam Bagg, MD: The avidity is suggestive of something that has gone awry, that has progressed. Histologically, this is reported to show a diffuse large B-cell lymphoma. It is usually, or ought to be, straightforward, to distinguish diffuse large B-cell lymphoma from chronic lymphocytic leukemia. But there are potential pathologic caveats that might mislead those who are less familiar with looking at CLL lymph nodes, since we usually diagnose the disease in peripheral blood or bone marrow. One feature that might be misinterpreted in chronic lymphocytic leukemia, even in the so-called chronic phase, is the disease histologically being characterized by pseudofollicular proliferation centers, which are collections of cells that don’t look like CLL cells. They’re collections of larger cells that resemble prolymphocytes but do not resemble large cells. To a pathologist who is not familiar with looking at CLL lymph nodes, those may be concerning for large cell transformation. They do not indicate large cell transformation. It is very important to be aware of their existence.

Things become a little bit concerning when you see enlarged proliferation centers. Historically, there was a lot of literature on the prognostic relevance of large proliferation centers. That sort of went out of vogue. More recently, there are data to suggest that large confluent proliferation centers are a poor prognosticator. And yet it is still not indicative of Richter transformation. So, it’s important to be aware of that. And, of course, in any phase of CLL, you will see a sprinkling of large cells. That’s fine and is almost expected in typical chronic lymphocytic leukemia, histologically. But when the cells form sheaths and sizable sheaths, only at that point should one be making a diagnosis of diffuse large B-cell lymphoma. It’s not always the case, but one assumes that large cell lymphoma reflects transformation of the underlying chronic lymphocytic leukemia.

I think the current thinking is that approximately 25% of diffuse large B-cell lymphomas that arise in the setting of chronic lymphocytic leukemia are actually clonally unrelated to the CLL itself. It’s important, when you encounter a diffuse large B-cell lymphoma in the setting of CLL, to do appropriate studies, if you are able to, to see whether they are clonally related. One could simply do that, with appropriate tools, by looking at the clonal immunoglobulin heavy-chain gene rearrangement to see whether they are similar or different. Understandably, that has some prognostic relevance with a de novo diffuse large B-cell lymphoma perhaps being less aggressive than one that is transformed from an underlying CLL. I’m not qualified to address whether that translates into a different therapeutic approach, but I think it’s important to know whether that is, in fact, the case—whether it is a true transformation or just a second clonally unrelated DLBCL.

Matthew S. Davids, MD, MMSc: Those are all very important points. Clearly, the pathology is key here. Dr. Wierda, this is a patient who has a very good clinical story for Richter syndrome. We see that the LDH is markedly elevated, and we see this PET/CT finding of an SUV of 15. Are there any new data that might inform us as to whether this could just be ibrutinib progression in CLL? Or is this a slam dunk for Richter, without the biopsy?

William Wierda, MD, PhD: Well, if a patient has a clinical presentation of Richter transformation, we really need to do a biopsy. We use PET/CT to help direct biopsy. Many times, in a patient who actually has Richter transformation, they’ll present with a nodal area that is rapidly enlarging. The clinical suspicion is there. Other things that lead to an increased suspicion for Richter transformation are elevated LDH, and patients usually look sick. They have fever and fatigue. So, we do the PET/CT. We’ve done an analysis on outcomes for patients who we suspect have Richter, who have had a PET/CT. We noted that the outcomes, whether or not we show that there’s Richter, are poor if there are active nodes.

We will typically biopsy patients who have an SUV of 10 or higher. In our analysis, the patients who had diagnosed Richter and who had an elevated SUV without a diagnosis of Richter did similarly poorly with salvage therapy. That said, I think it’s important to do a biopsy to clarify whether or not the patient has a Richter transformation. It’s also important to know whether or not it’s clonally related. We do know that the patients who have a clonally unrelated transformation do better, clinically, than patients who have a clonally related transformation.

Matthew S. Davids, MD, MMSc: I think that’s so important. The therapy will be different if it’s CLL versus Richter, even though the outcomes may still be poorer for the patients with CLL. So, that’s a really important point.

William Wierda, MD, PhD: We didn’t talk about it, but the other thing to note is that although it’s not technically referred to as Richter transformation, you can have a transformation event with a different histology—that’s Hodgkin histology, which is uncommon.

Matthew S. Davids, MD, MMSc: Right.

Transcript edited for clarity.
 
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