Ajay K. Gopal, MD

 We’ve come a long way in the treatment of follicular lymphoma. The prognosis is improved. We understand how to risk stratify based not only on the baseline characteristics, but probably more importantly, on the initial remission duration. We now have agents that are not traditional chemotherapies or chemo-antibody therapies, but we still have work to do. Especially for that 20% of patients who have that early relapse, we really need to improve outcomes for those who have a poor prognosis.

I’m very hopeful regarding some of the agents and classes of drugs that are on the horizon. One class of drugs are the T-cell engagers. These are often called bispecific antibodies that basically bring the lymphoma cell in proximity to the T cell—they’re often CD20 and CD3 bispecific, which is a common construct—and these have shown some early promise in follicular lymphoma. We’re hoping that this would be an off-the-shelf immunotherapy that could be effective for patients, particularly those who have chemo-refractory disease.

Taking it up a notch, something that’s already approved for other B-cell malignancies are CAR T cells, chimeric antigen receptor modified T cells. I’m sure many of you are familiar with these. There are studies that are ongoing or have been completed, and we’re awaiting their results in terms of having this as an option, particularly for the highest-risk and fit patients. Someone has to be relatively fit to make it through this therapy. This would be a relatively small subset of follicular lymphoma patients. Nevertheless, for those who really need another option, there are some who could potentially benefit from this therapy. This is potentially a curative strategy.

There are a number of small molecules such as EZH2 inhibitors. We’re hoping that small subset of patients with 

 mutations can benefit from agents such as tazemetostat. Then, there are a number of other novel compounds in the pipeline that we’re looking forward to.

So I’m very hopeful regarding where we’re going with follicular lymphoma. We can say to the majority of patients that their lifespan should not be shortened with this diagnosis, and we can manage this as kind of a nuisance disease. But there are still some patients for which this disease will shorten their lifespan, and I’m hopeful that our new approaches will improve their outcomes.

Case:A 69-Year-Old Woman With Follicular Lymphoma

A 69-year-old woman complains of a 5-month history of fatigue, decreased appetite and a 10-bs. weight loss

PE: right axillary and bilateral cervical lymph nodes palpated ~ 3 cm; spleen palpable 4 cm below costal margin



Labs: ANC 1.6 x 109/L, WBC 11.8 x 109/L, 40% lymphocytes, Hb 8.9 g/dL, plt 98 x 109/L, LDH 308 U/L, B2M 3.7 µg/mL; HBV negative

Excisional biopsy of the lymph node on IHC showed CD 20+, CD 10+, BCL2+; follicular lymphoma grade 2

Bone marrow biopsy showed paratrabecular lymphoid aggregates, 45% involvement

PET/CT showed enlargement of right axillary lymph nodes (3.1 cm, 3.2 cm), diffusely enlarged nodes in the retroperitoneal and lumbar lymph nodes

She was treated with R-CHOP for 6 cycles with rituximab maintenance; achieved partial response

5 months later she complained of increasing fatigue

Repeat PET/CT revealed progression of disease

She was started on bendamustine + obinutuzumab for 6 cycles and continued maintenance obinutuzumab

Repeat lymph node biopsy remained grade 1-2 follicular lymphoma

9 months later she complained of chills and low-grade fever

She was started on idelalisib 150 mg PO BID

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Novel Therapies for Patients With Follicular Lymphoma

 Idelalisib was evaluated in a large single-arm phase 2 trial that specifically looked at patients with indolent B-cell lymphomas. This included follicular lymphoma, small lymphocytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma. This trial required patients to be exquisitely high risk. They had to have disease that was refractory to both alkylating agents and rituximab, meaning less than a partial response or a relapse within 6 months of receiving one of these agents.

This was a single-arm trial, and all patients were dosed with idelalisib given at 150 mg PO BID [orally twice a day]. They continued therapy until either progressive disease or unacceptable toxicity, and stopped therapy at the discretion of the patient or treating physician.

This was the first registrational trial for drugs in this class, and this showed a rapid time to response—a median of 1.9 months—an overall response rate in the follicular lymphoma cohort of 57% with 6% CRs [complete responses], and a duration of response of 12.5 months. For the entire cohort, the median progression-free survival in the patients with follicular lymphoma was 11 months.

Since that time, there have been 2 additional PI3-kinase inhibitors approved for follicular lymphoma. We have a second oral PI3-kinase inhibitor called duvelisib. In the DYNAMO trial, which looked at a comparable patient population, duvelisib had an overall response rate of 42%. A third one, an intravenous PI3K inhibitor, copanlisib, in a lower-risk follicular lymphoma group, showed an overall response rate of 59%. This drug is given intravenously on days 1, 8, and 15 of a 4-week cycle.

Let’s look a little bit at managing patients on PI3-kinase inhibitors. They do have a unique adverse effect profile. As I mentioned before, there’s probably an immunomodulatory component to these drugs. It was found early on that patients who have not had any prior chemotherapy had evidence of transaminitis. This was probably an inflammatory hepatitis, and it improved with immunosuppression, prednisone, and holding the drug.

We can still see that on occasion, even in the third-line and beyond settings. In general, it’s important to follow the guidelines associated with the elevation in transaminases. Typically, if there is up to 5 times the upper limit of normal elevation in transaminases, patients can simply be observed, typically with weekly laboratory tests. If it’s anywhere from about 5 to 20 times the upper limit of normal, we’ll typically try to either hold the drug or reduce the dose to 100 mg twice a day. The vast majority of patients can actually get through this early period, but it does require that we monitor their labs about every other week during that initial period, even for patients who are well with no adverse events.

The other notable adverse event for idelalisib, and really for the PI3-kinase inhibitors in general, is GI [gastrointestinal] toxicity. There’s early diarrhea that is usually a little easier to manage. Nevertheless, you need patients to report this. There can also be a late onset of more inflammatory type of diarrhea that comes on at about 6 months or so. It’s important to educate your patients to report their adverse effects, and make sure your clinic team, including nurses, understands that when a patient calls after being on idelalisib, or really any PI3-kinase inhibitor for a number of months and suddenly develops diarrhea, this needs to be investigated. There is a standard algorithm that’s available for managing the diarrhea, but many patients, over half of the patients in the initial study, could actually get back on their dosing of idelalisib despite developing GI toxicity.

These are unique adverse events, but they can be managed. There are readily available algorithms for adjusting the dosing, as well as potential temporary holds for these adverse events.

Treating R/R Follicular Lymphoma With PI3K Inhibitors

 Not every patient will need third- or fourth-line therapy. It somewhat depends on the underlying disease, but also the age of the patient at diagnosis. If we think about patients with early progression, about 20% of all patients with follicular lymphoma have progressive disease within 2 years. Then we think of the median age of diagnosis being in the early 60s, although this patient is a bit older. Those factors come into play in terms of the likelihood of having to ever get to third-line therapy. In my practice, in an academic referral center, I do see many patients needing third-line therapy or beyond, so this is a common situation, unfortunately, in our clinical practice.

Fortunately, we have a number of agents and approaches for patients needing third-line therapy. It somewhat depends on what they’ve had previously. If they haven’t had lenalidomide, that’s still on the list. I mentioned before ibritumomab tiuxetan as a potential option for the appropriate patient. But we have an entire class of drugs now called the PI3-kinase inhibitors. There are 3 drugs approved. The first was idelalisib, and this was evaluated in the DELTA study.

The PI3-kinase inhibitors probably have 2 mechanisms of action. The initial thought was that this was primarily a drug that blocks the B-cell receptor signaling pathway. PI3 kinase is part of that. However, more recent data suggest that these drugs are probably also immunomodulatory. They tend to suppress regulatory T cells, probably reflected somewhat in their adverse effect profile, and may also suppress myeloid-derived suppressor cells. So the actual function is not completely clear, but there’s probably a combination of direct effect on B-cell receptor signaling and some immunomodulation.

PI3K Inhibition for R/R Follicular Lymphoma

 Again, this patient had a relatively short initial remission duration. The patient falls into about the 20% range of patients who have early progression. Fortunately, the patient did not have evidence of histologic transformation. Nevertheless, this is still a fairly poor prognosis group, even if you take out the transformed patients. The question here really is, what do you do? Most people, including myself, try to do something other than chemoimmunotherapy when we see a patient with early progression. I will concede that the data are not available as to what the right answer is, but more of the same treatment is probably not the right answer, unless maybe you’re using chemotherapy as a stepping-stone to something more definitive. The more definitive thing might be something like an autologous transplant. This patient, based on age, might be borderline regarding their candidacy for an autotransplant. There can be very fit 69-year-olds, and age is not a strict exclusion, but nevertheless, this patient might be in the upper limit of age for an autologous transplant.

If I’m not using a chemoimmunotherapy approach, I would typically try to do something that’s different. Thankfully, we now have some other, different options. One option is the combination of lenalidomide/rituximab. In a comparative trial to rituximab alone, that combination showed a significant benefit in progression-free survival. Now, the major caveat to those data is that was a rituximab-sensitive patient population. This patient is not rituximab-sensitive. The patient progressed on rituximab maintenance. And so, I think we would expect our results to be inferior to what we’ve seen in the AUGMENT study.

Another approved agent is ibritumomab tiuxetan. This is a radioimmunoconjugate, a single infusion, for patients who have low bone marrow involvement. It can be quite effective and has very low toxicity in the second-line setting, particularly for older patients.

I really try to think about clinical trials for these patients, however, and this is the exact type of patient I would refer to a major center for a clinical trial.

Follicular Lymphoma: Treating Early Progression

 One important consideration when approaching any patient with an indolent B-cell malignancy, most commonly follicular lymphoma, is to ask the question of whether the patient needs to be treated. In this case, I think it was pretty clear-cut. The patient was symptomatic. The patient had cytopenias, and there was really a clear-cut indication for treatment. But this approach really applies at every relapse. This is a chronic disease, and none of the therapies that we’re discussing today are primarily curative. We’re trying to relieve symptoms from the disease. At every time point when there’s disease progression, one has to ask the question, is there an indication for treatment? I think there clearly was for this patient.

There are a couple of other important points illustrated in this case. One question is, after initial remission induction—in this case, R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone]—are there prognostic factors that we can look at? This patient did not achieve a complete remission after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone induction, and this bodes quite poorly for patients. We really have to be on guard that this patient is going to have a short remission, with or without maintenance therapy.

A second major question is whether there is a benefit to using maintenance therapy. To date, there’s really been no trial in follicular lymphoma that showed an overall survival benefit associated with rituximab maintenance, or any anti-CD20 antibody maintenance, for that matter, as part of initial therapy. For this reason, I think one can go either way on maintenance, and it comes down to a long discussion with patients about the pros versus cons of maintenance.

The pro to using maintenance therapy might be that you would extend their remission duration. However, this may come with chronic B-cell depletion and some low-grade infections and hypogammaglobulinemia.

For the vast majority of my patients, I don’t give maintenance therapy based on the fact that there is no overall survival advantage. And there are some data that demonstrate you actually get the same amount of mileage with fewer doses of rituximab by not giving maintenance therapy.

Maintenance Therapy for Follicular Lymphoma

Clearly, this is a high-risk follicular lymphoma case. This is a patient who had early relapse after R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] chemotherapy, and had a very short remission duration after second-line chemoimmunotherapy. We can look a little bit at the prognostic factors. If we try to glean the FLIPI [Follicular Lymphoma International Prognostic Index] score from this case, likely a score of 5—age, stage, hemoglobin, extra nodal sites, and LDH [lactate dehydrogenase]—we would expect about a 35% 10-year overall survival in this situation. There is another FLIPI categorization called FLIPI2 that takes into account beta2 microglobulin and marrow involvement. So she probably had a FLIPI2 score of 4 here, which would have given her about a 20% 5-year overall survival. Both of these are relatively high-risk from the start.

However, the FLIPI and FLIPI2 scores don’t necessarily drive us to choose 1 therapy over another. The scores just give us a general idea of prognosis. She had a very appropriate treatment. I suspect rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone was chosen potentially because her disease was behaving badly, and she may have had some symptoms that might have worried the treating physician about some occult transformation. So she received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, but unfortunately had a very short remission after that.

This patient falls into this category of progression of disease by 24 months, and it’s been looked at by a number of groups. Really, not surprisingly, early progression portends a very poor outcome.

An important point from this case is that the treating physician was very diligent and performed a repeat biopsy. The thing to remember with early progression is there is a high rate of transformation. If you look at the PRIMA data, 37% of the patients who had progression within 1 year actually had evidence of histologic transformation to diffuse large B-cell lymphoma. If we look at the BC Cancer agency data of patients treated after bendamustine/rituximab, those who progressed within 2 years had a 76% rate of histologic transformation. So it is very important, in terms of management, to make sure you repeatedly biopsy patients with an early relapse. Our practice is, whenever possible, we want to make sure we know what we’re dealing with when we are changing from one therapy to another. This physician did the right thing. The physician did a biopsy, did not see evidence of early transformation, and saw, still, persistent follicular lymphoma and went on to a second-line regimen.

Now, I think the bigger question in this situation is, should one go with a chemoimmunotherapy-based regimen when you’ve already had a short remission after prior chemotherapy? I think that’s a matter of debate. Bendamustine/obinutuzumab is an approved approach, particularly for those with rituximab-refractory disease. But unfortunately, this patient did not get much of a remission after the bendamustine/obinutuzumab strategy.

Ajay K. Gopal, MD | Authors

Articles

Novel Therapies for Patients With Follicular Lymphoma

Treating R/R Follicular Lymphoma With PI3K Inhibitors

PI3K Inhibition for R/R Follicular Lymphoma

Follicular Lymphoma: Treating Early Progression

Maintenance Therapy for Follicular Lymphoma

Follicular Lymphoma: Prognostic Scoring and Treatment Decisions