ONCAlert | Upfront Therapy for mRCC

Case 3: Elderly Patient With Treatment-Naive CLL

Targeted Oncology
Published Online:1:00 PM, Tue February 11, 2020


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Anthony Mato, MD, MSCE: This is a 79-year-old male who complains of increasing bouts of fatigue and intermittent moderate to severe abdominal pain. The patient has a pretty significant past medical history of type 2 diabetes that’s controlled with insulin. Patient is obese with a sedentary lifestyle, has a history of gastric ulcers that were treated with H. [Helicobacter] pylori but are not currently bleeding at this time—also former heavy alcohol use and cigarette use, 20-year smoking history but quit about 10 years ago. CLL [chronic lymphocytic leukemia] was diagnosed about 2 years ago—relatively asymptomatic at the time. Patient was managed with active observation. Patient has a little bit of renal dysfunction likely related to some of the medical issues, with a creatinine clearance of 64 mL/min/1.73 m2.

Physical exam reveals bulky adenopathy in the cervical and axillary chains, as well as inguinal lymphadenopathy, causing some symptoms to the patient. A CT [computed tomography] image and chest x-ray are performed, which show a large right pleural effusion, as well as multistation bulky lymphadenopathy, hepatomegaly, and splenomegaly, and let’s say the spleen is approximately 18 cm in size. This patient has a little bit of an unusual presentation in that they’re presenting with a symptomatic pleural effusion, and patient undergoes thoracentesis and pleural fluid analysis is positive for leukemic cells. Just out of curiosity, is this something you see in the lab very often or is this an infrequent occurrence?

Nupam A. Patel, MD: We do see leukemia that’s found within the pleural fluid. It is a common thing.

Shuo Ma, MD, PhD: I want to raise a precaution. Most of the time, in a patient who has body fluid analysis—actually virtually all CLL patients, if they have active disease—when you do a bodily fluid analysis, you’re almost always going to be able to find CLL there. What I use to tell whether this is actually not really pathologic—more of a malignant effusion versus just CLL cells being there as an innocent bystander—I look at the percentage of the CLL cells. If you see that the body fluid is primarily T cells, and CLL cells are just a small proportion, then I think that’s probably not pathologic. If they’re accounting for the majority of the cells, then you might think otherwise. I’ve seen very rarely true cases of malignant effusion from CLL.

Anthony Mato, MD, MSCE: Nontransformed CLL.

Shuo Ma, MD, PhD: Right.

Anthony Mato, MD, MSCE: Totally agree with you. I’ve seen it, but it’s 1 case a year, so this is a very unusual case. What’s your experience?

Sameer A. Parikh, MBBS: At the recently concluded iwCLL [International Workshop on Chronic Lymphocytic Leukemia] meeting, we had data on pleural effusions as a presentation or the presenting feature of CLL and patients needing thoracentesis to actually establish a diagnosis of CLL. Off our database, we identified less than 20 patients who had that presentation. It’s extremely rare. Like you mentioned, you have to be very careful because, like this patient, our patients have multiple comorbidities: they have heart failure, they have pneumonia, they have other reasons to have pleural effusion. Before attributing the effusion to CLL, we have to be careful to exclude alternative etiologies.

Anthony Mato, MD, MSCE: It’s a little bit off topic, but I would say the most difficult and dangerous fluid analysis that leads to wrong medical decision making is a CSF [cerebrospinal fluid], where there are so many reasons to have these bystanders or passengers present and almost never—in fact, maybe never—is it really due to malignant infiltration of the CSF as a cause for the presence of those cells.

Sameer A. Parikh, MBBS: This is in stark contrast to, for example, if you see large cell lymphoma; then it is diagnostic of CNS [central nervous system] involvement or even involvement of the pleural space, because it would be unlikely that you would see large cells in spaces like pleural fluid, for example, or CSF. I think it is important to recognize that it’s different depending on what kind of histology you find in these fluid analyses.

Anthony Mato, MD, MSCE: We digressed a little bit from the case, but I think that’s interesting conversation. The patient does have a CBC [complete blood cell count] performed at this time. The white blood cell count is 83 000, predominantly lymphocytes. The hemoglobin is 9.1. We should have said this earlier, but when thinking about these hemoglobins, we probably need an MCV [mean corpuscular volume] to really try to decide if this is disease related or iron deficiency, for example, or some other causes or nutritional deficiency. Platelets are 108 000, neutrophils are 1700, LDH [lactate dehydrogenase] is 250, and β2‑microglobulin is markedly elevated at 8.9. So this patient has molecular testing, including FISH [fluorescence in situ hybridization] with no abnormalities and is IGHV [immunoglobulin heavy chain variable]-unmutated. Any comments there in terms of the workup that’s been performed?

Nupam A. Patel, MD: The workup here, although the FISH is negative, FISH can sometimes be overemphasized. I think you really need to do a karyotype on top of this because FISH is a very targeted entity. Whereas a karyotype—you may find other alterations, which may change your prognosis, which you won’t find on the FISH if it is negative.

Anthony Mato, MD, MSCE: You just opened a box for the conversation here. It says patient did have a bone marrow, but I didn’t mention that those were tests, whether they came from bone marrow or peripheral blood. So karyotype—you get a peripheral blood sample sent to you in the lab. Do you go ahead and perform it? How do you do it? Do you stimulate? Do you insist on a marrow sample? What’s the yield from peripheral blood? How do we do this?

Nupam A. Patel, MD: Peripheral blood—we typically routinely we do not do a karyotype on that unless specifically asked.

Anthony Mato, MD, MSCE: You need a marrow then.

Nupam A. Patel, MD: We would typically want the marrow to do that.

Anthony Mato, MD, MSCE: We’ll probably get a couple different answers here, but from a pathologist’s perspective, we call these things complex. That has certain meaning to it. What does it mean to you? What does it mean to all of us?

Nupam A. Patel, MD: The pathologic definition is whenever you have greater than 3 abnormalities, that is considered complex karyotype.

Anthony Mato, MD, MSCE: We just, interestingly, had a paper that we submitted where all of a sudden the definition changed last week and it was now 5 or more abnormalities. I’m just curious. In our practices, are we doing 3 or 5? Where do we feel the data are?

Sameer A. Parikh, MBBS: I think we do CpG [5'-C-phosphate-G-3'] stimulated karyotype mostly in the bone marrow. Although we could do it in the peripheral blood, it’s typically not done. I think we would do it. Bone marrow is generally obtained only in patients who need treatment as opposed to patients with a new diagnosis. That is a little bit different compared to what this patient has, which is advanced-stage disease, and so they’re likely to need therapy. I think a stimulated karyotype is probably a reasonable thing to do.

I think we’ve started to define this as high complexity versus low complexity, and so high is more than 5, and between 3 and 5 is low complexity, and no complexity or noncomplex would be less than 3 abnormalities. You’re right, I think these data keep evolving; they keep changing their definitions. But I do think that more than 3 would be considered as standard sort of abnormal in most cases.

Anthony Mato, MD, MSCE: Totally agree. What do you think?

Shuo Ma, MD, PhD: I think at least the previous standard has been, you can do that on peripheral blood with…CpG stimulated karyotyping and 3 or more unrelated cytogenetic abnormalities defined as complex.

Anthony Mato, MD, MSCE: This patient does have a bone marrow biopsy. There’s diffuse infiltration by CLL and that’s the likely explanation for why the patient has the cytopenia that they do. A decision was made to start ibrutinib and we discussed this already. The dose was 420 mg once daily in a continuous fashion with the intent to treat until progression or an adverse event. Unfortunately, this patient did have some adverse events that need to be considered. They developed grade 3 neutropenia relatively early in the course of therapy, which ultimately resolved with management, and that management was a dose interruption, and then the patient was started at a lower dose.

I also should mention that this patient developed grade 3 arthralgias, which is a relatively common toxicity associated with BTK [Bruton tyrosine kinase] inhibitors. It’s been best described in patients who were treated with ibrutinib, and for that reason as well, the patient had a dose reduction and they resolved to grade 2 or grade 1. So ibrutinib is better tolerated.

Transcript edited for clarity.


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Anthony Mato, MD, MSCE: This is a 79-year-old male who complains of increasing bouts of fatigue and intermittent moderate to severe abdominal pain. The patient has a pretty significant past medical history of type 2 diabetes that’s controlled with insulin. Patient is obese with a sedentary lifestyle, has a history of gastric ulcers that were treated with H. [Helicobacter] pylori but are not currently bleeding at this time—also former heavy alcohol use and cigarette use, 20-year smoking history but quit about 10 years ago. CLL [chronic lymphocytic leukemia] was diagnosed about 2 years ago—relatively asymptomatic at the time. Patient was managed with active observation. Patient has a little bit of renal dysfunction likely related to some of the medical issues, with a creatinine clearance of 64 mL/min/1.73 m2.

Physical exam reveals bulky adenopathy in the cervical and axillary chains, as well as inguinal lymphadenopathy, causing some symptoms to the patient. A CT [computed tomography] image and chest x-ray are performed, which show a large right pleural effusion, as well as multistation bulky lymphadenopathy, hepatomegaly, and splenomegaly, and let’s say the spleen is approximately 18 cm in size. This patient has a little bit of an unusual presentation in that they’re presenting with a symptomatic pleural effusion, and patient undergoes thoracentesis and pleural fluid analysis is positive for leukemic cells. Just out of curiosity, is this something you see in the lab very often or is this an infrequent occurrence?

Nupam A. Patel, MD: We do see leukemia that’s found within the pleural fluid. It is a common thing.

Shuo Ma, MD, PhD: I want to raise a precaution. Most of the time, in a patient who has body fluid analysis—actually virtually all CLL patients, if they have active disease—when you do a bodily fluid analysis, you’re almost always going to be able to find CLL there. What I use to tell whether this is actually not really pathologic—more of a malignant effusion versus just CLL cells being there as an innocent bystander—I look at the percentage of the CLL cells. If you see that the body fluid is primarily T cells, and CLL cells are just a small proportion, then I think that’s probably not pathologic. If they’re accounting for the majority of the cells, then you might think otherwise. I’ve seen very rarely true cases of malignant effusion from CLL.

Anthony Mato, MD, MSCE: Nontransformed CLL.

Shuo Ma, MD, PhD: Right.

Anthony Mato, MD, MSCE: Totally agree with you. I’ve seen it, but it’s 1 case a year, so this is a very unusual case. What’s your experience?

Sameer A. Parikh, MBBS: At the recently concluded iwCLL [International Workshop on Chronic Lymphocytic Leukemia] meeting, we had data on pleural effusions as a presentation or the presenting feature of CLL and patients needing thoracentesis to actually establish a diagnosis of CLL. Off our database, we identified less than 20 patients who had that presentation. It’s extremely rare. Like you mentioned, you have to be very careful because, like this patient, our patients have multiple comorbidities: they have heart failure, they have pneumonia, they have other reasons to have pleural effusion. Before attributing the effusion to CLL, we have to be careful to exclude alternative etiologies.

Anthony Mato, MD, MSCE: It’s a little bit off topic, but I would say the most difficult and dangerous fluid analysis that leads to wrong medical decision making is a CSF [cerebrospinal fluid], where there are so many reasons to have these bystanders or passengers present and almost never—in fact, maybe never—is it really due to malignant infiltration of the CSF as a cause for the presence of those cells.

Sameer A. Parikh, MBBS: This is in stark contrast to, for example, if you see large cell lymphoma; then it is diagnostic of CNS [central nervous system] involvement or even involvement of the pleural space, because it would be unlikely that you would see large cells in spaces like pleural fluid, for example, or CSF. I think it is important to recognize that it’s different depending on what kind of histology you find in these fluid analyses.

Anthony Mato, MD, MSCE: We digressed a little bit from the case, but I think that’s interesting conversation. The patient does have a CBC [complete blood cell count] performed at this time. The white blood cell count is 83 000, predominantly lymphocytes. The hemoglobin is 9.1. We should have said this earlier, but when thinking about these hemoglobins, we probably need an MCV [mean corpuscular volume] to really try to decide if this is disease related or iron deficiency, for example, or some other causes or nutritional deficiency. Platelets are 108 000, neutrophils are 1700, LDH [lactate dehydrogenase] is 250, and β2‑microglobulin is markedly elevated at 8.9. So this patient has molecular testing, including FISH [fluorescence in situ hybridization] with no abnormalities and is IGHV [immunoglobulin heavy chain variable]-unmutated. Any comments there in terms of the workup that’s been performed?

Nupam A. Patel, MD: The workup here, although the FISH is negative, FISH can sometimes be overemphasized. I think you really need to do a karyotype on top of this because FISH is a very targeted entity. Whereas a karyotype—you may find other alterations, which may change your prognosis, which you won’t find on the FISH if it is negative.

Anthony Mato, MD, MSCE: You just opened a box for the conversation here. It says patient did have a bone marrow, but I didn’t mention that those were tests, whether they came from bone marrow or peripheral blood. So karyotype—you get a peripheral blood sample sent to you in the lab. Do you go ahead and perform it? How do you do it? Do you stimulate? Do you insist on a marrow sample? What’s the yield from peripheral blood? How do we do this?

Nupam A. Patel, MD: Peripheral blood—we typically routinely we do not do a karyotype on that unless specifically asked.

Anthony Mato, MD, MSCE: You need a marrow then.

Nupam A. Patel, MD: We would typically want the marrow to do that.

Anthony Mato, MD, MSCE: We’ll probably get a couple different answers here, but from a pathologist’s perspective, we call these things complex. That has certain meaning to it. What does it mean to you? What does it mean to all of us?

Nupam A. Patel, MD: The pathologic definition is whenever you have greater than 3 abnormalities, that is considered complex karyotype.

Anthony Mato, MD, MSCE: We just, interestingly, had a paper that we submitted where all of a sudden the definition changed last week and it was now 5 or more abnormalities. I’m just curious. In our practices, are we doing 3 or 5? Where do we feel the data are?

Sameer A. Parikh, MBBS: I think we do CpG [5'-C-phosphate-G-3'] stimulated karyotype mostly in the bone marrow. Although we could do it in the peripheral blood, it’s typically not done. I think we would do it. Bone marrow is generally obtained only in patients who need treatment as opposed to patients with a new diagnosis. That is a little bit different compared to what this patient has, which is advanced-stage disease, and so they’re likely to need therapy. I think a stimulated karyotype is probably a reasonable thing to do.

I think we’ve started to define this as high complexity versus low complexity, and so high is more than 5, and between 3 and 5 is low complexity, and no complexity or noncomplex would be less than 3 abnormalities. You’re right, I think these data keep evolving; they keep changing their definitions. But I do think that more than 3 would be considered as standard sort of abnormal in most cases.

Anthony Mato, MD, MSCE: Totally agree. What do you think?

Shuo Ma, MD, PhD: I think at least the previous standard has been, you can do that on peripheral blood with…CpG stimulated karyotyping and 3 or more unrelated cytogenetic abnormalities defined as complex.

Anthony Mato, MD, MSCE: This patient does have a bone marrow biopsy. There’s diffuse infiltration by CLL and that’s the likely explanation for why the patient has the cytopenia that they do. A decision was made to start ibrutinib and we discussed this already. The dose was 420 mg once daily in a continuous fashion with the intent to treat until progression or an adverse event. Unfortunately, this patient did have some adverse events that need to be considered. They developed grade 3 neutropenia relatively early in the course of therapy, which ultimately resolved with management, and that management was a dose interruption, and then the patient was started at a lower dose.

I also should mention that this patient developed grade 3 arthralgias, which is a relatively common toxicity associated with BTK [Bruton tyrosine kinase] inhibitors. It’s been best described in patients who were treated with ibrutinib, and for that reason as well, the patient had a dose reduction and they resolved to grade 2 or grade 1. So ibrutinib is better tolerated.

Transcript edited for clarity.
Copyright © TargetedOnc 2020 Intellisphere, LLC. All Rights Reserved.