John P. Leonard, MD

 A number of ongoing trials are directed at trying to better meet the needs of patients with follicular lymphoma. One area is that early progressor group. About 20% of patients present with recurrence within 2 years of initial therapy. That’s a group of patients who have a less favorable overall survival. We are working hard to identify those groups of patients as well as decide if they should be treated differently.

There’s an ongoing SWOG-led study that’s focused on this patient population, looking for biomarkers. They’re trying to sort out if they should be treated with chemoimmunotherapy, a PI3-kinase-based approach, or a lenalidomide-based approach, essentially asking if 1 of these novel approaches should be prioritized in patients with early progression.

In the other group of patients—the majority of patients who are not likely to die from follicular lymphoma but die with follicular lymphoma—quality of life is the key priority. If you can identify a patient and know that they aren’t going to die from the disease, then managing their disease in the long term is an important goal. Trying to tailor treatment to the patient’s optimal quality of life would be an important objective.

Finally, we have a number of new agents that are coming along in follicular lymphoma. We have new PI3 kinase inhibitors, antibody-drug conjugates, bispecific antibodies, CAR [chimeric antigen receptor] T-cell therapies. We have tazemetostat, an EZH2 inhibitor. There are a number of other approaches that clearly have activity in follicular lymphoma. The key challenges are to sort out for when and for whom we should be using these drugs.

That said, the future is bright. We’re going to see lots of progress over the coming years for the treatment of patients with follicular lymphoma.

 Case: A 72-Year-Old Woman With Follicular Lymphoma

A 71-year-old woman complains of a 5-month history of occasional fevers, decreased appetite, fatigue, and an unintentional 7-lbs. weight loss

PE: palpable left axillary lymph nodes ~ 4 cm and bilateral cervical lymph nodes ~ 3 cm; spleen palpable 4.5 cm below costal margin 
 

/L, 42% lymphocytes, Hb 9.6 g/dL, plt 100 x 10

/L, LDH 325 U/L, B2M 3.7 µg/mL; HBV negative 

Excisional biopsy of the axillary lymph node on IHC showed CD 20+, CD 3+, CD5+, CD 10+, BCL2+; follicular lymphoma grade 2 

Bone marrow biopsy showed paratrabecular lymphoid aggregates, 45% involvement 

Molecular genetics: t(14;18) (q32;q21) 

PET/CT showed enlargement of left axillary, mediastinal, and bilateral para-aortic lymphadenopathy (4.2 cm, 5.3 cm, 3.6 cm, and 3.5 cm respectively) 

She was treated with R-CHOP for 6 cycles; continued rituximab maintenance 375 mg/m

6 months later, she complained of increasing frequency of fevers and chills 

Repeat PET/CT revealed progression of disease 

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

Repeat lymph node biopsy grade 2 follicular lymphoma 

12 months later, she complained of increased weight loss and fatigue 

She was started on idelalisib 150 mg PO BID and achieved partial response 

She experienced grade 2 diarrhea, which was successfully managed 

Videos

Dr John P. Leonard highlights ongoing clinical trials and therapies of interest in the follicular lymphoma pipeline and explains how progress in the field will help address ongoing treatment challenges.

Addressing Treatment Gaps in Follicular Lymphoma

 There are now significant data regarding the safety and efficacy of idelalisib as well as with copanlisib and duvelisib. I have the most experience with idelalisib, having participated in some of the original clinical trials, and it’s been around the longest. But I would say the other PI3 kinase inhibitors also have important and useful data as well and are active and safe agents.

Idelalisib has about a 50% response rate in patients with recurrent follicular lymphoma, lasting about a year. These are patients who have disease that is often resistant to rituximab or to prior chemotherapy. I would say the data with copanlisib and duvelisib are also in that same ballpark.

The adverse-effect profile with idelalisib is something that’s important to keep in mind if you’re using this agent. I do have some patients who have been on it for years. It can be a useful agent for some patients. But you need to be aware of the adverse-effect profile when managing and monitoring these patients.

The most common adverse-effect issues that come up include cytopenias and risk of infections. There have been some cases of pneumocystis and CMV [cytomegalovirus], so you do need to monitor and keep those possibilities in mind. Liver enzyme abnormalities occasionally occur. When that happens, you typically would pause the drug and then resume it when the liver enzymes have resolved or returned to normal.

One of the issues that can come up is diarrhea with idelalisib. This tends to be a bit later in onset—after several months of treatment. It really depends on the severity of the diarrhea and the response to symptomatic management that patients have.

One obviously wants to be careful about ruling out other causes of diarrhea, including infectious diarrhea. You should take a history of issues that may be associated with an infection. Certainly, avoiding lactose, drinking lots of fluids, and using the typical BRAT [bananas, rice, apples, toast] diet can be helpful if diarrhea occurs. Obviously, you can pause the drug. Loperamide can also be used in a number of different settings.

If the diarrhea resolves, the drug can be resumed and can often be resumed at the same dose; or one can reduce the dose, particularly if it’s been more severe.

Other options in more severe cases include giving steroids like oral prednisone or budesonide, which can be effective. Obviously, in the more severe cases dose reduction is more important. In some cases, discontinuation may be needed.

Diarrhea can also occur with other PI3 kinase inhibitors, including duvelisib. Other adverse-effect profiles are class specific. Copanlisib, as an example, is associated with more hypertension and more glucose abnormalities. These are less of an issue with the more delta-specific agents.

John P. Leonard, MD, of Weill Cornell Medicine and NewYork-Presbyterian Hospital, comments on the safety and efficacy data for PI3K inhibitors for relapsed/refractory follicular lymphoma treatment and shares advice on best practices for monitoring patients on therapy and managing any treatment-related adverse events.

PI3K Inhibitors for Relapsed/Refractory FL: Safety & Efficacy

 There are a number of choices for patients like this 1 in third-line therapy. If we practice long enough and have patients who have had follicular lymphoma long enough, there are many people who will go on to receive third-, fourth-, and even later-line therapy over the course of their disease, depending on their individual situation.

Some of the same options that we discussed earlier would be things to at least consider depending on the patient’s prior therapy. Giving the patient bendamustine-based therapy or CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]–based therapy would be reasonable. Again, you have rituximab and obinutuzumab. These would come up among our choices. We would also think about lenalidomide if the patient hadn’t received this class of treatment in the past. Sometimes retreatment is used. 

In patients with more resistant disease, the PI3 kinase inhibitors are choices that show value for a number of patients. We have data that suggest they can be helpful in patients with disease that’s resistant to rituximab, to chemotherapy.

The first of these that was approved was idelalisib, which is an oral focused on the PI3K-delta isoform. We also have copanlisib and duvelisib approved in this setting. These would also be possibilities for this particular case.

Perhaps one chose idelalisib in this situation because it’s been around the longest. But the other choices would also be reasonable. It’s notable that idelalisib and duvelisib are oral agents, whereas copanlisib is given intravenously on a weekly schedule with some breaks. So the route of administration is different. Because of the PI3 kinase selectivity, the toxicity profile is a bit different.

But in particular, the oral route of administration is something that many patients appreciate with idelalisib as well as duvelisib among these choices. Copanlisib might be a better choice for patients who have issues with compliance or for whom in-office treatment with an infusion might be preferred. These are all very reasonable treatments to consider.

I will also add that there are other chemotherapy drugs. A stem cell transplant could be used in certain patients. This is not as likely to be employed in older patients, but an autologous stem cell transplant is still an important treatment modality for patients with recurrent follicular lymphoma. We also have tazemetostat, an EZH2 inhibitor, approved for patients with recurrent follicular lymphoma as well in certain situations, particularly more effective if they have an EZH2 mutation.

There are a number of choices. Certainly, idelalisib would have been a reasonable choice, as was selected in this patient case, but there are a number of others that could have been chosen as well.

Treatment options available for patients with relapsed/refractory follicular lymphoma in later-line settings and factors that impact the selection of a PI3K inhibitor over other types of therapies.

Relapsed/Refractory FL: Third-Line and Beyond Treatment Options

 There are a number of agents available at the time of first relapse, and many of them are also available at subsequent relapses. The key prognostic information comes from the time to progression after the first therapy. Those patients who progress within 2 years have a particularly less favorable prognosis than those patients who progress after chemoimmunotherapy after 2 years.

The duration of the first response, particularly after chemoimmunotherapy, is quite important in looking at long-term outcomes. I would generally look at a patient and look at their duration of response to their up-front therapy as a key factor in determining what I do next. If a patient progresses early, within that 2-year time frame, I’m particularly concerned. In fact, about half of those patients have transformation at the time of progression. That’s a patient who I might be more prone to rebiopsy or at least get a PET [positron emission tomography] scan to look for the presence of transformation.

If transformation is there, a more aggressive approach is with anthracyclines, if not already given, or perhaps an autotransplant. Those would be things I would think about.

The majority of patients will progress later—after 2 years from their initial therapy. Those are patients who have a relatively favorable prognosis. There are a number of options for these patients, depending on what they had before. One could often give single-agent rituximab if they had a long remission. We know that lenalidomide-rituximab can be useful and is associated with a PFS [progression-free survival] benefit and a higher response rate when combined with rituximab as second-line therapy in rituximab-relapsed patients.

Other options include chemoimmunotherapy again. If the patient had CHOP up front, you could use bendamustine-based therapy at relapse, or vice versa. If the patient had bendamustine up front, you could consider CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or other combination chemotherapies in the relapsed setting.

The use of obinutuzumab vs rituximab is another important distinction. Based on the time to progression and if the patient has more resistant disease, I might be more prone to use obinutuzumab in the more resistant disease setting, and rituximab in the more relapsed setting.

But all of these really figure into the decision as to what I would choose as second-line therapy. 

Obviously, the indications for therapy include, is the patient at risk for transformation? Do they need treatment at all in the relapsed setting? All these factors figure into what we would choose in the relapsed setting for patients with follicular lymphoma.

Recommendations for appropriately assessing patients with follicular lymphoma with disease progression after frontline treatment and options to consider as second-line therapy.

Second-Line Treatment for Relapsed Follicular Lymphoma

 A couple of different questions need to be explored when assessing a patient with newly diagnosed follicular lymphoma. First, does the patient need therapy? There are a number of different criteria that are used for this purpose. Certainly, the BNLI [British National Lymphoma Investigation] and GELF [Groupe l’Etude des Lymphomes Folliculaires], 2 European groups, have come up with some criteria. But to some degree, these are common sense. Does the patient have multiple sites of disease? Does the patient have bulky disease? Do they have symptoms? Do they have cytopenias? Do they have evidence of organ compromise that is present?

This patient does have symptoms. She does have anemia. I think that, when you look at the totality of her presentation, she would need to undergo therapy. 

The second question is, what treatment is appropriate for this patient? In my mind, the main cutoff is, are we going to give the patient single-agent rituximab? This might be an option for a patient with a lower tumor burden, perhaps minor symptoms. Or are we going to treat the patient with chemoimmunotherapy? 

This is a patient who has more symptoms, more disease, more disease burden. And this might be a patient—based on her high-risk FLIPI [Follicular Lymphoma International Prognostic Index] score—for whom we might be more prone to give chemoimmunotherapy based on her symptoms and her extent of disease, particularly her anemia.

That being said, there is a bit of a gray area and room for discussion—and some would say negotiation with the patient—to decide if you’re going to use single-agent therapy or a combination approach.

Among the available treatment options for this patient, I would most likely be leaning toward bendamustine-rituximab or R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. This patient has a significant amount of disease. If I was more worried about transformation, I would certainly use R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. If I was less concerned about transformation, or perhaps if this was a younger patient, I might be a little more prone to use R [rituximab]–bendamustine.

There are some concerns about immunosuppression with bendamustine and tolerability issues in older patients, but I would say this is quite open to discussion and interpretation. R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or R [rituximab]–bendamustine would be reasonable choices for this person.

The substitution of obinutuzumab for rituximab has been associated with a little more toxicity, a little more infection, a little more cytopenias. However, we see about a 5% improvement in progression-free survival [PFS] when you look over time. So obinutuzumab would be a reasonable choice as well. 

Some have argued that obinutuzumab might not be a great choice with bendamustine because of this infection risk, and that could be taken into consideration. Additionally, the use of obinutuzumab is given with maintenance because the data with obinutuzumab has been better established with up-front therapy when a maintenance regimen has been used.

In general, the use of maintenance therapy can be used after frontline treatment. That’s an individualized decision. Some patients like maintenance therapy, whether it’s rituximab or obinutuzumab, based on the PRIMA study with rituximab because there is a significant progression-free survival benefit. However, there is not an overall survival benefit. So some people would argue that omission of maintenance is perfectly fine, and re-treatment—perhaps with rituximab or a combination therapy—is appropriate and will have the same effect and benefit with regard to ultimate overall survival.

This patient could or could not receive maintenance therapy. It’s an open question and something I would discuss with the patient. Some patients like the PFS benefit and don’t mind coming in for additional treatment over 2 years. Others say, “I want to take a break. If I relapse I can get more therapy at the time of progression.”

The question of how to follow a patient in this regard is another important question. Typically, I would see such a patient, get a PET [positron emission tomography] scan and a physical assessment and labs at the end of treatment. And if the patient was in complete remission [CR], I would expect that that patient would be likely to have an ongoing CR for 5 years or longer on average.

That’s a patient who I would typically see every 3 to 4 months for the first couple of years, and then maybe every 6 months, and then maybe once a year, ultimately, because clinical monitoring is the key part of the follow-up. There’s not really a big role for surveillance imaging in patients who are asymptomatic and doing well. These patients tend to have long remissions, generally speaking. Additionally, the anxiety and other issues associated with surveillance imaging really suggest that it’s not needed.

Most relapses for these patients that are clinically significant are associated with issues that are clinically evident, such as symptoms or physical findings or laboratory abnormalities. Generally speaking, if a patient was in CR after frontline therapy, I would expect that they would likely have a long remission—at least 5 years, on average.

Frontline treatment options available to treat newly diagnosed follicular lymphoma, based on a patient’s presentation, and recommendations for offering maintenance therapy following first-line treatment.

Frontline Treatment for Newly Diagnosed Follicular Lymphoma

 This is a 71-year-old patient with newly diagnosed follicular lymphoma who has indications for therapy. She has significant disease. She has splenomegaly. She has cytopenias. We want to be clear that she has follicular lymphoma and her diagnosis appears to be accurately made.

We want to think about if she has evidence of transformation, because that would change our treatment approach. She had a PET [positron emission tomography] scan that showed no evidence of transformation, at least to the extent that her SUV [standard uptake value], in the range of 8 to 10, is more consistent with follicular lymphoma. However, she does have a slight elevation in LDH [lactate dehydrogenase], so we do have to think about transformation, and that’s something that one needs to think about in any patient, particularly one starting on therapy.

Overall, once we’ve established the diagnosis, staged the patient, and sorted out her extent of disease, a crucial issue is, does she need treatment at all? We’ll get into these details in a minute, but it appears that she does. She’s anemic. She has symptoms. So this is a patient who would need treatment.

We have a couple of different possibilities to think about in this case.

When we look at a newly diagnosed patient with follicular lymphoma, there are some prognostic issues that are useful. In particular, the IPI [International Prognostic Index] has been used over many years. More recently, the FLIPI [Follicular Lymphoma International Prognostic Index] is helpful. The FLIPI includes nodes. No-LASH is a way to remember it: number of nodal regions, LDH elevation, age over 60, stage, and hemoglobin.

There are specific cutoff values. This patient has a number of adverse FLIPI factors, including sites of disease, age over 60, elevated LDH, anemia, and stage of disease. She would fall into an adverse-risk group with respect to her FLIPI score.

That being said, some would argue that patients with an adverse or high-risk FLIPI score should be treated more aggressively. This is a patient who clearly does need treatment. One might argue that a more aggressive treatment might make sense, although to be clear, the use of the FLIPI score is quite limited in choosing therapy. We don’t know that we necessarily should treat higher-risk patients differently from lower-risk patients. One would argue that this is a patient who has a higher-risk score, so she should probably be treated with chemoimmunotherapy, vs rituximab alone as an alternative.

Important considerations when diagnosing follicular lymphoma, including the rationale for assessing patients’ FLIPI score and looking for any signs of histologic transformation.  

John P. Leonard, MD | Authors

Articles

Addressing Treatment Gaps in Follicular Lymphoma

PI3K Inhibitors for Relapsed/Refractory FL: Safety & Efficacy

Relapsed/Refractory FL: Third-Line and Beyond Treatment Options

Second-Line Treatment for Relapsed Follicular Lymphoma

Frontline Treatment for Newly Diagnosed Follicular Lymphoma

Current Criteria Used to Help Diagnose Follicular Lymphoma