Diagnostic Work-Up in Follicular Lymphoma

Jonathan Friedberg, MD:I think this patient had a very standard work-up. You know, general blood testing, including LDH [lactate dehydrogenase]. Some people also perform a beta-2 microglobulin, which in some series is also prognostic. As far as imaging, I think PET [positron emission tomography or] CT [computed tomography] is now the standard imaging procedure. You don’t need to do other imaging studies.

Bone marrow biopsies are still in question. I think that for many patients, they really don’t affect management. For patients who do present with cytopenias, it can be helpful to understand the etiology of the cytopenia. The extent of bone marrow involvement can be hard to predict based on blood counts. And it’s often the case that the bone marrow is involved, so you would expect that at least 60% to 70% of the time.

In follicular lymphoma, similar to what I said about clinical risk factors, unlike diffused large B-cell lymphoma, we’re really starting to incorporate genetics and molecular diagnostics into a risk stratification system for follicular lymphoma. That’s not really the case. In general, follicular lymphoma should be a fairly straightforward diagnosis that has a classic [histological] appearance. It is very important to grade the follicular lymphoma. Grade 1 and 2 disease is considered low-grade disease. It has to do with how many larger cells are seen within each high-powered field.

Grade 3 disease is split up into grade 3a and 3b. Grade 3b is essential diffused large B-cell lymphoma and it should be treated as such. There’s some controversy about grade 3a and the optimal treatment for that. Many do approach that with a more aggressive chemotherapy regimen.

This patient had grade 2 disease. That’s typical and really behaves just like grade 1 disease. Beyond histological appearance and some very straightforward immunohistochemistry studies like CD10 andBCL2, there are not a lot of other studies that you really need to do for follicular lymphoma. I do think on the horizon there may be some additional tests that may end up being incorporated, but this is still preliminary. For example, EZH2 mutations are seen in a subset of follicular lymphoma. They may have a more favorable prognosis, but they also may be appropriate for certain precision medicine approaches. I think we’re on the cusp of using more testing, but at this point the standard testing is fairly limited.

There are a number of clinical prognostic scoring systems in follicular lymphoma—the FLIPI [Follicular Lymphoma International Prognostic Test], the FLIPI2 score. Then there’s this m7-FLIPI that incorporates some molecular information. All these are prognostic; I should emphasize they’re not really predictive. They have not been used to segregate treatments for patients. They can be helpful when you’re having a discussion with a patient on what they should expect as far as treatment. But at this point we really don’t use any of them to assign a specific therapeutic approach to a patient.

I always calculate a standard FLIPI on my patients. At some level that’s academic, and at some level it is helpful when I talk to a patient about what they might expect. But again, it’s a very vague expectation because there are patients with high-risk FLIPI who do well, and then there are patients with low-risk FLIPI who do less well.

The m7-FLIPI incorporates some sequencing information that we don’t do as a standard of care yet. But I think it’s the beginning as to what we hope will eventually evolve to be a more robust score that not only is prognostic but really predictive and allows us to choose appropriate patients for an appropriate therapy. Again, we’re not there yet, but that’s really where a lot of the research in follicular lymphoma is headed.

I think that 1 of the big research areas in follicular lymphoma is understanding why a subgroup of patients may be resistant to treatment, have early-disease progression, or not respond as you might expect. And there are clinical trials going on that have heavy correlative studies where they’re trying to bank tumors, not only at diagnosis but at the time of relapse, and understand what genetic changes or molecular changes are occurring that may predict for this inferior outcome.

Thus far it’s been hard to get a lot of those paired specimens to really understand it. I think there’s also a hope that with the technology that we have for the so-called liquid biopsy, or the circulating tumor DNA, that we may have an easier time following dynamically how the molecular changes are occurring that may ultimately help us understand why a disease becomes resistant to treatment.

One thing we do know about follicular lymphoma is that there are multiple clones within a patient at diagnosis. I think that explains to some degree the thinking as to why some patients may have inferior outcomes. There may be a resistant clone that may be present in small numbers.

In the context of these trials what we’re trying to do is gather paired specimens where at the time a patient has progression, we’re comparing the genetics and molecular features to the time at diagnosis, seeing what those changes are.

The other thing I would emphasize is that most patients with follicular lymphoma have several clones. And what often can occur is with treatment you’re treating the most sensitive of the clones, which may be over-representative in an initial biopsy. But a resistant clone that may be present in small numbers does propagate over time, particularly maybe with selective pressure from the treatment.

That makes follicular lymphoma particularly complex. Because if you simply do a lymph node sample and you look at the genomics of that lymph node, what you’re seeing is the genomics of the most represented clone. If there’s a very rare clone there, that is really the resistant clone, that is what’s going to cause a problem for the patient. It may be hard to find unless you’re really looking for it.

I think 1 of the things we’ve learned as we try to understand why patients are resistant and surprise us with inferior outcome is that this is a very complex disease, and it’s not necessarily going to be a straightforward problem to fix.

Transcript edited for clarity.

Case: A 59-Year-Old Man With Symptomatic Follicular Lymphoma

A 59-year-old man presented to his physician with a 10-lb weight loss and chronic night sweats for the past couple of months. He complained of intermittent fatigue but is able to maintain his current exercise regimen.

H & P

• PE: enlarged bilateral axillary lymph nodes; enlarged spleen, palpable
• CBC: WBC, 12 X 10⁴/L; platelets,103 X 10⁹/L; Hgb, 9.2 g/dL
• LDH: 400 U/L

Biopsy

• Excisional biopsy showed grade 2 follicular lymphoma; CD20+, CD10+
• Bone marrow biopsy; 60% involved

Imaging

• PET/CT showed widespread lymphadenopathy and a large splenic mass measuring 10 cm
• Diagnosis: Stage IV follicular lymphoma

Teatment

• Started on R-CHOP; tolerated induction well
• Post-therapy PET showed partial remission
• Followed by Rituximab maintenance until evidence of disease progression

Follow-up

• Core needle biopsy; performed confirmed persistent follicular lymphoma; no transformation
• PET at 12 months showed increased size of splenic mass
• ECOG, 0
• Patient started on obinutuzumab + bendamustine