Management of Chronic Lymphocytic Leukemia - Episode 7

Case 3: Elderly Patient With CLL, Mutated TP53 and NOTCH, Unmutated IgHV

April 26, 2018


William Wierda, MD, PhD:Now let’s move on to case No. 3. Matt?

Matthew S. Davids, MD, MMSc:This is a 75-year-old man who was diagnosed with CLL about 4 years ago. He was observed, over that time, with some modest progression of disease. Now he is coming in with increasing bouts of extreme fatigue, abdominal bloating, and some intermittent moderate to severe abdominal pain. This patient has significant comorbidities, including type 2 diabetes (requiring insulin), and on physical exam in the office, the patient really has bulky lymphadenopathy in both the cervical and axillary areas. On an abdominal CT scan, there’s a large right pleural effusion. There’s also bulky multistation lymphadenopathy, as well as hepatomegaly and splenomegaly.

A thoracentesis was performed. It was malignant. Laboratory evaluations revealed significant lymphocytosis with a total white blood cell count of 84,000. The patient was also significantly anemic (with a hemoglobin of 9.4) and was moderately thrombocytopenic. The LDH test was normal at that time, at 262. But the beta2microglobulin was very elevated. Some other molecular testing was performed, including FISH testing, which was normal. TheIGHVmutation status was unmutated. The patient was positive forZAP70and had somatic mutations in bothTP53and inNOTCH1. A bone marrow biopsy was performed at that time, and it showed diffuse infiltration by CLL. To start with this case, I want to talk to Dr. Bagg about what the prognosis might be, based on these molecular markers.

Adam Bagg, MD:In terms of the additional studies that were performed, these studies are not diagnostic studies. These are prognostic studies, and I think that’s important to make a note of. Abnormalities of chromosome 11q22 deletions, trisomy 12, deletion 13q14, and deletion 17p are usually looked at in a FISH panel.

The conventional karyotypic cytogenetic analysis is missing from this. It’s important not to lose sight of the fact that even though FISH is remarkably useful in picking up aberrations that may be missed on metaphase analysis, metaphase analysis remains important and is typically done on simulated cells to induce the neoplastic lymphocytes to divide. And so, for example, you may have a completely negative FISH panel, but cytogenetics may show a complex karyotype that would be prognostically relevant. It may show an immunoglobulin heavy-chain gene translocation 14q32, which may not be on the FISH panel, that may have prognostic relevance, too.

With regard to the actual mutational studies, the presence of an unmutated immunoglobulin heavy-chain gene variable sequence indicates that the CLL has not transited through the germinal center and that these patients with this flavor of CLL tend to have a worse prognosis. Positivity for thatZAP70is interesting. I’m not sure how many laboratories are still doing this, and maybe that’s a point of discussion to prognosticate in CLL?

In the early days of looking at immunoglobulin heavy-chain gene variable region mutation analysis, the testing was laborious and cumbersome. People looked for surrogates. One of the surrogates that emerged wasZAP70, with the expression ofZAP70correlating with unmutated immunoglobulin genes. There was also some literature to suggest thatZAP70, in and of itself, could be a prognostic variable, as well as some literature to suggest thatZAP70was an even more potent prognosticator than the presence or absence of immunoglobulin heavy-chain genes. Nowadays, with FISH panels and mutational panels, it has fallen by the wayside, in terms of being used and looked at on a routine basis.

The mutatedTP53gene, of course, indicates a poorer prognosis. Although they are often accompanied by a deletion of 17p, when the mutation is there, about 30% of patients have a mutation alone, without the deletion of the otherTP53gene detected by FISH.NOTCH1is one of the genes on small panels that can be looked at in patients with CLL. Other genes might beSF3B1,ATM, among many others.NOTCH1mutations, which were found in perhaps 5% to 10% of patients with CLL, are a poor prognosticator, in general terms. Some additional data suggest that it’s a risk factor for Richter transformation.

Matthew S. Davids, MD, MMSc:These prognostic factors are clearly important as we decide on which therapies to use. But certainly, another thing that’s important to consider is the comorbidities of the patient. Dr Jain, we know that there are less formal ways to assess this, as well as some formal ways to assess comorbidities, that are often used in clinical trials. Maybe you could briefly just take us through that?

Nitin Jain, MD:Sure. The assessment of comorbidities is important for patients with CLL, and I would say that was more relevant in the context of the chemoimmunotherapy era. The German CLL Study Group has typically used a scoring system that is based on different comorbidities. You can count the number of comorbidities that a patient has, such as heart disease, kidney disease, diabetes, other diseases, and hypertension. A score of more than 6 is considered high-risk. These patients are considered to be less suitable for chemoimmunotherapy. In our group, and in most centers in the United States, the age of the patient, their renal function status, and the performance status of a patient are typically more important factors that we look at. If you’re electing for chemoimmunotherapy, those are the decisions that come to mind. How old is the patient? If a patient has poor renal function, he or she may not be appropriate for intensive chemotherapy, such as FCR. These are things that I generally look at when I look at a patient, in terms of their comorbidities and how we assess them.

Matthew S. Davids, MD, MMSc:We’ve talked about a number of important prognostic factors—FISH, theIGHVstatus, and then these different somatic mutations. Often, they kind of line up. But this is kind of an unusual situation here. We have a patient who has aTP53mutation but does not have deletion 17p. The FISH is normal here.

Nitin Jain, MD:For sure, this is a bit unusual. I think that 90%, 95% of patients who have deletion 17p have a concomitantTP53mutation. Certainly, 5% to 10% of patients have a discordant result, where you have either deletion 17p or theTP53mutation, which appears to be the case here. Studies have shown that the presence of either one of them is a high-risk feature. This patient does not have deletion 17p but has mutatedTP53. So, the patient should be managed as a patient who has lost aTP53function. In the current era, he would be less suitable for chemoimmunotherapy.

Matthew S. Davids, MD, MMSc:Dr. Wierda, based on these prognostic markers and the other features of this case, what’s your suspicion, here, for the risk of Richter transformation?

William Wierda, MD, PhD:Based on the presence of theNOTCH1mutation, that puts the patient at higher risk for Richter transformation. TheTP53mutation, perhaps, puts the patient at a higher risk, although there are fewer clear data to make that association. The other feature, which we haven’t talked about yet, that makes this patient unusual is the malignant pleural effusion. That’s a high-risk feature. It is not necessarily a risk factor for Richter transformation, but the biology of the disease, for this patient, is a bit different from that of your typical patient who’s 75 years old with CLL. There is something different about these cells that gives them the propensity to collect in the pleural space and give a malignant pleural effusion. It is a higher-risk feature, clinically, having a malignant pleural effusion like this.

Transcript edited for clarity.