ONCAlert | Upfront Therapy for mRCC

Case 1: Newly Diagnosed CLL, IGHV-Unmutated

Targeted Oncology
Published Online:1:00 PM, Tue January 28, 2020


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Anthony Mato, MD, MSCE: Thank you for joining us for this Targeted Oncology® Virtual Tumor Board®, which is focused on Chronic Lymphocytic Leukemia. In today’s Targeted Oncology® Virtual Tumor Board® presentation, my colleagues and I will review 4 clinical cases. We will discuss an individualized approach to treatment for each patient and will review key trial data that impacts on our decisions.

I am Dr Anthony Mato, a hematologist/oncologist and director of the CLL program at Memorial Sloan Kettering Cancer Center in New York, New York.

Today, I am joined by Dr Shuo Ma, associate professor of medicine in Hematology and Oncology at the Feinberg School of Medicine at Northwestern University in Chicago, Illinois;

Dr Sameer Parikh, assistant professor of medicine, consultant in the Division of Hematology at the Mayo Clinic in Rochester, Minnesota;

And Dr Nupam Patel, assistant professor of pathology and laboratory medicine at the Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey.

Thank you for joining us. Let’s get started with our first case.

Shuo Ma, MD, PhD: I’ll start with the first case, I have a 66-year-old female patient who presented with complaints of weight loss and increasing fatigue. She has a past medical history of hypertension, which is well controlled with medication, otherwise healthy. One exam she was found to have axillary lymphadenopathy. Her spleen’s palpable, 4 cm below the left costal margin.

She’s ill-appearing, and because of fatigue, so that is impacting her daily activity. On the laboratory results we can see that she has elevated white cell count of 47,000. The majority of those are lymphocytes, 76%. She does have anemia and thrombocytopenia. Hemoglobin 8.7; platelet count is 115. Her lactate dehydrogenase (LDH) is slightly elevated at 250. Her ß2 microglobulin was elevated at 4.3.
 
The flow cytometry was done because of the lymphocytosis and it shows a monoclonal B-cell population that is CD5+, CD20+, and CD23+. Maybe it will help us to interpret the flow cytometry and let us know what is important for diagnosis.

Nupam A. Patel, MD: When we look at flow cytometry and we get a population that is monoclonal and we’re looking at a B-cell population which also expresses CD5, the 2  things that definitely come into mind are chronic lymphocytic leukemia [CLL] and mantle cell lymphoma. We have a couple of other markers to additionally kind of distinguish them. CD23 is probably the most classic of those. CD23 is positive in CLL while it is negative in mantle cell lymphoma. There’s other things that we can use like the expression profile in CD20 and the expression profile in the light chain. You typically have a dimmer profile expression in CD20 in the light chain, whereas that’s conversely true in mantle cell lymphoma.

A newer marker that we use is CD200. CD200 is classically positive and CLL while negative in mantle cell lymphoma. Based on what we have this is a CLL.

Anthony Mato, MD, MSCE: Do you think it’s mandatory for every patient to have CCND1 translocation checked, or is not a requirement?

Nupam A. Patel, MD: It’s not a part of the standard fluorescence in situ hybridization
[FISH] panel in a lot of labs, but many people do use it. I think it is helpful because you do have some atypical mantle cell cases that are out there which may carry that translocation.

Shuo Ma, MD, PhD: In our institution the 11;14 translocation is part of the CLL FISH panel, and I think it’s mandatory to rule out mantle cell lymphoma before we make our confirmation diagnosis for CLL.

Anthony Mato, MD, MSCE: I totally agree.

Sameer A. Parikh, MBBS: It’s the same thing at our institution as well as 11;14 as a part of the standard CLL FISH Panel.

Anthony Mato, MD, MSCE: I also agree with what you said. We’ve seen many patients who have a CLL FISH panel that sort of one of the commercial lab for example that doesn’t necessarily include that. So it’s important that; we probably should mention it in all of our cases that that’s tested and was negative.

Shuo Ma, MD, PhD: I agree. We did have a FISH Panel done, and she doesn’t not have the 11;14 translocation but she does have a deletion 11q. Nupam, can you tell us a bit more about how the FISH panel is done?

Nupam A. Patel, MD: The standard across the board what you’ll typically find is a CLL FISH panel; you’ll have about 5 or 6 different probes. They usually target like chromosomes 11, 12, 13, 17, and some may include chromosome 6. Like we mentioned just before, they may include for the in translocation in mantle cell lymphoma. This patient had deletion of 11q, which we typically associate with a poorer prognosis, so that’s what we find.

Shuo Ma, MD, PhD: What do you find in your practice when you see a patient with 11q?

Anthony Mato, MD, MSCE: I mean if patients are reading what’s going on online, for example, 11q is typically associated with a poorer prognosis. I think it’s always important to frame that in the context of its poor prognosis regarding specific regimens, and that’s really patients who were treated with chemoimmunotherapy.

My general feeling is that it sort of mandates a little bit of a shift away from chemotherapy for these patients, but it probably has no impact on prognosis when you’re treated with a novel targeted agent. A Bruton tyrosine kinase [BTK] inhibitor for example might be the best example.

Sameer A. Parikh, MBBS: I think the context of poor prognosis needs to be understood with respect to is this a patient who doesn’t meet criteria for therapy? It’s likely that maybe then this patient is likely to have faster progression of disease needing therapy. Like Anthony Mato, MD, MSCE, mentioned, you know there is now data to suggest that with ibrutinib therapy this, quote/unquote, poor prognosis isn’t really as poor as it used to be there in chemoimmunotherapy. I think we have to be mindful as we talk about prognosis and deletion of 11q patients.

Anthony Mato, MD, MSCE: That’s true for any prognostic markers. You have to keep in mind what patient population it was defined in I think in order to really determine whether it applies to a particular patient.

Shuo Ma, MD, PhD: Historically all of those with prognostic markers are looking at overall survival for those patients. But that was mostly in the era of immunochemotherapy, so that might be changing. I would say that a patient with 11q deletion CLL tends to have a faster pace of disease progression.

They can present with more bulky adenopathy, especially abdominal adenopathy. There’s probably a shorter time from the time of diagnosis until they receive the first treatments. That probably still holds true. It may no longer be an important predictive marker for treatment, which we’re going to touch on later on.

There is another important prognostic marker that we’ll recommend to test for. In this case it’s the IGVH mutation status. This patient was found to have an IGVH-unmutated status. Could you comment on that?  

Nupam A. Patel, MD: What we’re looking for is whether the IGVH, the heavy chain is mutated or unmutated. That kind of refers to the cell of origin of the CLL, whether it has gone through the germinal center or not the germinal center. Unmutated is classically as a poorer prognosis because that’s those that have not gone through the germinal centers; whereas as mutated is more of the better prognosis as they’ve gone through the germinal center.

Shuo Ma, MD, PhD: Could you comment on how the test has gone; what is the cut-off for defining unmutated versus mutated?

Nupam A. Patel, MD: In the older days it was tougher to do because it is sequenced, and that’s why flow cytometrically they developed and they found some markers, CD30 and ZAP70, which have, basically a surrogate for IGVH. Nowadays it’s a lot easier to do and, therefore, we just sequence that.

Nupam A. Patel, MD: Typically, when we’re looking at whether it’s mutated or; mutated, unmutated, we want to see a 2% difference from the wild-type.

Shuo Ma, MD, PhD: In clinical practice do you guys do the IGVH mutation analysis for newly-diagnosed patients? Or what do you think is the helpful for?

Anthony Mato, MD, MSCE: We do it pretty universally in all of our patients because I do think it does affect disease biology. I think, you know we’ll talk about it in other cases where we’re using next-generation sequencing (NGS) for minimal residual disease [MRD], but I think having this data available then helps us to track disease response later on based on some of our MRD assessments that we have available.

Sameer A. Parikh, MBBS: A number of our patients are previously untreated at the time when we first see them, they don’t meet indications for therapy. I think the IGVH mutation status is a very powerful indicator of the biology of the underlying disease that allows us to predict how fast their disease is likely to progress, and so be also routinely obtain in all our patients.

One thing I’ll add to whatever has been said is that unlike many of the other markers that do not change over time, IGVH—excuse me, that do change over time, IGVH mutation status stays pretty constant, and so you don’t have to repeat this prognostic marker over times. If you’ve gotten it once, that typically stays constant over the patient’s disease course.

Anthony Mato, MD, MSCE: It’s important to highlight that although we all seem to check this relatively universally in our practices, the data from registries in this country suggest only between 5% and 7% of patients ever have this tested before a treatment decision is made. In practice I think it’s probably not happening as often as it should be. The surrogates, I don’t know if you want to comment on it, are probably not perfectly associated with the IGHV mutational status. I don’t think ZAP70 is a good enough surrogate in 2020 for.

Nupam A. Patel, MD: Actually a lot of labs have gone away from ZAP70. And ZAP 70 has a lot of issues with stability and even interlaboratory reproducibility, including CD38. CD38, as mentioned before, it can show varying levels of expression whereas it’s maybe negative where it’s positive, where the IGVH is always going to give you the true answer.

Anthony Mato, MD, MSCE: In my former practice I asked them to remove both ZAP70 and CD38 from the panel because I don’t, I personally haven’t ever seen it affect clinical decision making at this point.

Sameer A. Parikh, MBBS: I think we’ve also removed both of those markers. You know, the most of, the most comprehensive prognostic index, the International Prognostic Index [for Chronic Lymphocytic Leukaemia], which has its own limitations but in that prognostic index they used about 28 variables to try and define prognosis. In that IGVH was one of the factors that was important in a multivaried analysis; but CD38 and ZAP70 were not important. So that’s why a lot of people have moved away from checking ZAP70 and CD38 for that reason.

Nupam A. Patel, MD: There is a newer marker which has not been completely adopted by the United States, it’s a CD49D, but that has shown a better reproducibility and stability as compared to the CD38 and ZAP70.

Shuo Ma, MD, PhD: Is there also a surrogate marker for IGVH unmutated status?

Nupam A. Patel, MD: It does have an association with it, but it’s not truly a surrogate.

Anthony Mato, MD, MSCE: We have the ability to test it, but I haven’t really adopted that because I feel like the most important tests are the ones that we’re talking about where you would, that have a direct influence on clinical decision making. So the FISH does, the IGHV mutational status does. We didn’t talk about it, but next generation sequencing does. CD49D, CD38, I really don’t know how to interpret them and with the current data and make a decision based on those results.

Transcript edited for clarity.


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Anthony Mato, MD, MSCE: Thank you for joining us for this Targeted Oncology® Virtual Tumor Board®, which is focused on Chronic Lymphocytic Leukemia. In today’s Targeted Oncology® Virtual Tumor Board® presentation, my colleagues and I will review 4 clinical cases. We will discuss an individualized approach to treatment for each patient and will review key trial data that impacts on our decisions.

I am Dr Anthony Mato, a hematologist/oncologist and director of the CLL program at Memorial Sloan Kettering Cancer Center in New York, New York.

Today, I am joined by Dr Shuo Ma, associate professor of medicine in Hematology and Oncology at the Feinberg School of Medicine at Northwestern University in Chicago, Illinois;

Dr Sameer Parikh, assistant professor of medicine, consultant in the Division of Hematology at the Mayo Clinic in Rochester, Minnesota;

And Dr Nupam Patel, assistant professor of pathology and laboratory medicine at the Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey.

Thank you for joining us. Let’s get started with our first case.

Shuo Ma, MD, PhD: I’ll start with the first case, I have a 66-year-old female patient who presented with complaints of weight loss and increasing fatigue. She has a past medical history of hypertension, which is well controlled with medication, otherwise healthy. One exam she was found to have axillary lymphadenopathy. Her spleen’s palpable, 4 cm below the left costal margin.

She’s ill-appearing, and because of fatigue, so that is impacting her daily activity. On the laboratory results we can see that she has elevated white cell count of 47,000. The majority of those are lymphocytes, 76%. She does have anemia and thrombocytopenia. Hemoglobin 8.7; platelet count is 115. Her lactate dehydrogenase (LDH) is slightly elevated at 250. Her ß2 microglobulin was elevated at 4.3.
 
The flow cytometry was done because of the lymphocytosis and it shows a monoclonal B-cell population that is CD5+, CD20+, and CD23+. Maybe it will help us to interpret the flow cytometry and let us know what is important for diagnosis.

Nupam A. Patel, MD: When we look at flow cytometry and we get a population that is monoclonal and we’re looking at a B-cell population which also expresses CD5, the 2  things that definitely come into mind are chronic lymphocytic leukemia [CLL] and mantle cell lymphoma. We have a couple of other markers to additionally kind of distinguish them. CD23 is probably the most classic of those. CD23 is positive in CLL while it is negative in mantle cell lymphoma. There’s other things that we can use like the expression profile in CD20 and the expression profile in the light chain. You typically have a dimmer profile expression in CD20 in the light chain, whereas that’s conversely true in mantle cell lymphoma.

A newer marker that we use is CD200. CD200 is classically positive and CLL while negative in mantle cell lymphoma. Based on what we have this is a CLL.

Anthony Mato, MD, MSCE: Do you think it’s mandatory for every patient to have CCND1 translocation checked, or is not a requirement?

Nupam A. Patel, MD: It’s not a part of the standard fluorescence in situ hybridization
[FISH] panel in a lot of labs, but many people do use it. I think it is helpful because you do have some atypical mantle cell cases that are out there which may carry that translocation.

Shuo Ma, MD, PhD: In our institution the 11;14 translocation is part of the CLL FISH panel, and I think it’s mandatory to rule out mantle cell lymphoma before we make our confirmation diagnosis for CLL.

Anthony Mato, MD, MSCE: I totally agree.

Sameer A. Parikh, MBBS: It’s the same thing at our institution as well as 11;14 as a part of the standard CLL FISH Panel.

Anthony Mato, MD, MSCE: I also agree with what you said. We’ve seen many patients who have a CLL FISH panel that sort of one of the commercial lab for example that doesn’t necessarily include that. So it’s important that; we probably should mention it in all of our cases that that’s tested and was negative.

Shuo Ma, MD, PhD: I agree. We did have a FISH Panel done, and she doesn’t not have the 11;14 translocation but she does have a deletion 11q. Nupam, can you tell us a bit more about how the FISH panel is done?

Nupam A. Patel, MD: The standard across the board what you’ll typically find is a CLL FISH panel; you’ll have about 5 or 6 different probes. They usually target like chromosomes 11, 12, 13, 17, and some may include chromosome 6. Like we mentioned just before, they may include for the in translocation in mantle cell lymphoma. This patient had deletion of 11q, which we typically associate with a poorer prognosis, so that’s what we find.

Shuo Ma, MD, PhD: What do you find in your practice when you see a patient with 11q?

Anthony Mato, MD, MSCE: I mean if patients are reading what’s going on online, for example, 11q is typically associated with a poorer prognosis. I think it’s always important to frame that in the context of its poor prognosis regarding specific regimens, and that’s really patients who were treated with chemoimmunotherapy.

My general feeling is that it sort of mandates a little bit of a shift away from chemotherapy for these patients, but it probably has no impact on prognosis when you’re treated with a novel targeted agent. A Bruton tyrosine kinase [BTK] inhibitor for example might be the best example.

Sameer A. Parikh, MBBS: I think the context of poor prognosis needs to be understood with respect to is this a patient who doesn’t meet criteria for therapy? It’s likely that maybe then this patient is likely to have faster progression of disease needing therapy. Like Anthony Mato, MD, MSCE, mentioned, you know there is now data to suggest that with ibrutinib therapy this, quote/unquote, poor prognosis isn’t really as poor as it used to be there in chemoimmunotherapy. I think we have to be mindful as we talk about prognosis and deletion of 11q patients.

Anthony Mato, MD, MSCE: That’s true for any prognostic markers. You have to keep in mind what patient population it was defined in I think in order to really determine whether it applies to a particular patient.

Shuo Ma, MD, PhD: Historically all of those with prognostic markers are looking at overall survival for those patients. But that was mostly in the era of immunochemotherapy, so that might be changing. I would say that a patient with 11q deletion CLL tends to have a faster pace of disease progression.

They can present with more bulky adenopathy, especially abdominal adenopathy. There’s probably a shorter time from the time of diagnosis until they receive the first treatments. That probably still holds true. It may no longer be an important predictive marker for treatment, which we’re going to touch on later on.

There is another important prognostic marker that we’ll recommend to test for. In this case it’s the IGVH mutation status. This patient was found to have an IGVH-unmutated status. Could you comment on that?  

Nupam A. Patel, MD: What we’re looking for is whether the IGVH, the heavy chain is mutated or unmutated. That kind of refers to the cell of origin of the CLL, whether it has gone through the germinal center or not the germinal center. Unmutated is classically as a poorer prognosis because that’s those that have not gone through the germinal centers; whereas as mutated is more of the better prognosis as they’ve gone through the germinal center.

Shuo Ma, MD, PhD: Could you comment on how the test has gone; what is the cut-off for defining unmutated versus mutated?

Nupam A. Patel, MD: In the older days it was tougher to do because it is sequenced, and that’s why flow cytometrically they developed and they found some markers, CD30 and ZAP70, which have, basically a surrogate for IGVH. Nowadays it’s a lot easier to do and, therefore, we just sequence that.

Nupam A. Patel, MD: Typically, when we’re looking at whether it’s mutated or; mutated, unmutated, we want to see a 2% difference from the wild-type.

Shuo Ma, MD, PhD: In clinical practice do you guys do the IGVH mutation analysis for newly-diagnosed patients? Or what do you think is the helpful for?

Anthony Mato, MD, MSCE: We do it pretty universally in all of our patients because I do think it does affect disease biology. I think, you know we’ll talk about it in other cases where we’re using next-generation sequencing (NGS) for minimal residual disease [MRD], but I think having this data available then helps us to track disease response later on based on some of our MRD assessments that we have available.

Sameer A. Parikh, MBBS: A number of our patients are previously untreated at the time when we first see them, they don’t meet indications for therapy. I think the IGVH mutation status is a very powerful indicator of the biology of the underlying disease that allows us to predict how fast their disease is likely to progress, and so be also routinely obtain in all our patients.

One thing I’ll add to whatever has been said is that unlike many of the other markers that do not change over time, IGVH—excuse me, that do change over time, IGVH mutation status stays pretty constant, and so you don’t have to repeat this prognostic marker over times. If you’ve gotten it once, that typically stays constant over the patient’s disease course.

Anthony Mato, MD, MSCE: It’s important to highlight that although we all seem to check this relatively universally in our practices, the data from registries in this country suggest only between 5% and 7% of patients ever have this tested before a treatment decision is made. In practice I think it’s probably not happening as often as it should be. The surrogates, I don’t know if you want to comment on it, are probably not perfectly associated with the IGHV mutational status. I don’t think ZAP70 is a good enough surrogate in 2020 for.

Nupam A. Patel, MD: Actually a lot of labs have gone away from ZAP70. And ZAP 70 has a lot of issues with stability and even interlaboratory reproducibility, including CD38. CD38, as mentioned before, it can show varying levels of expression whereas it’s maybe negative where it’s positive, where the IGVH is always going to give you the true answer.

Anthony Mato, MD, MSCE: In my former practice I asked them to remove both ZAP70 and CD38 from the panel because I don’t, I personally haven’t ever seen it affect clinical decision making at this point.

Sameer A. Parikh, MBBS: I think we’ve also removed both of those markers. You know, the most of, the most comprehensive prognostic index, the International Prognostic Index [for Chronic Lymphocytic Leukaemia], which has its own limitations but in that prognostic index they used about 28 variables to try and define prognosis. In that IGVH was one of the factors that was important in a multivaried analysis; but CD38 and ZAP70 were not important. So that’s why a lot of people have moved away from checking ZAP70 and CD38 for that reason.

Nupam A. Patel, MD: There is a newer marker which has not been completely adopted by the United States, it’s a CD49D, but that has shown a better reproducibility and stability as compared to the CD38 and ZAP70.

Shuo Ma, MD, PhD: Is there also a surrogate marker for IGVH unmutated status?

Nupam A. Patel, MD: It does have an association with it, but it’s not truly a surrogate.

Anthony Mato, MD, MSCE: We have the ability to test it, but I haven’t really adopted that because I feel like the most important tests are the ones that we’re talking about where you would, that have a direct influence on clinical decision making. So the FISH does, the IGHV mutational status does. We didn’t talk about it, but next generation sequencing does. CD49D, CD38, I really don’t know how to interpret them and with the current data and make a decision based on those results.

Transcript edited for clarity.
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