Christopher R. Flowers, MD

 This patient’s situation addressed one of the key unmet needs with follicular lymphoma, and that’s patients who experience early relapse. I’ve been engaged in a US intergroup trial that evaluates those 3 arms with therapies for those patients who experience early relapse. I think that’s a very important trial to accrue patients to, to help answer this question.

The other unmet needs that are being addressed are those patients with aggressive forms of relapse or transformation.

CAR [chimeric antigen receptor] T cells are another promising therapy that is available for patients with follicular lymphoma, and I think new trials need to be explored to ascertain where those might be best utilized in the relapsed and refractory setting, particularly for patients who experience more aggressive disease.

There are now many new, novel targeted immunotherapies for patients with follicular lymphoma, and we’re moving into an era where chemotherapy-free regimens may be possible for patients in the first line of therapy and with each subsequent line of relapse.

It’s a very promising time for new therapies and new clinical trials for patients with follicular lymphoma.

Case:A 77-Year-Old Man With Follicular Lymphoma

A 77-year-old man complains of a 4-month history of occasional fevers, decreased appetite, and an unintentional 7-lbs. weight loss

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



Labs: ANC 1.5 x 109/L, WBC 10.6 x 109/L, 42% lymphocytes, Hb 10.1 g/dL, plt 100 x 109/L, LDH 325 U/L, B2M 3.3 µg/mL; HBV negative

Bone marrow biopsy showed lymphoid aggregates, 35% involvement

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)

He was treated with R-CHOP for 6 cycles; continued rituximab maintenance 375 mg/m3; achieved partial response

6 months later he complained of increasing frequency of fevers

Repeat PET/CT revealed progression of disease

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

Repeat lymph node biopsy grade 2 follicular lymphoma

8 months later he complained of increased weight loss

He was started on idelalisib 150 mg PO BID

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Follicular Lymphoma Management: Future Directions

 The pivotal trial that led to the approval of idelalisib was led by a good friend and colleague, Ajay Gopal, MD, and published in 

 in 2014. That was a multi-institutional trial of the single-agent PI3-kinase inhibitor idelalisib, given as a single arm in that trial.

In that trial, the drug was administered to patients with relapsed/refractory follicular lymphoma when those patients had relapsed after both rituximab and, typically, cyclophosphamide. Those patients moved on to receive this PI3-kinase inhibitor in that setting.

In this relapsed/refractory population, we saw an overall response rate for patients above 40%, with a duration of response—it was quite meaningful for this population—of more than a year for the majority of patients.

When we think about the adverse events associated with idelalisib, those tend to be associated both with the acute administration of the drug and related to inflammatory toxicities, or activation of T cells, in particular.

Some of those acute events can be in the form of diarrhea, which is typically acute while the drug is being administered. That’s one that typically happens relatively shortly after the administration of the drug and typically goes away if you stop the drug. And then if you restart the drug, it does not recur.

Along those same lines, patients can sometimes experience nausea or fatigue associated with the administration of the drug. The later kinds of toxicities we also worry about are associated with inflammatory toxicities—the so-called itises associated with idelalisib or the other PI3-kinase inhibitors. There we can see transaminitis, or elevation of the liver function tests. Those also typically go away if you stop the drug. And if you restart at a lower dose, those often do not recur.

There is a second kind of diarrhea that is inflammatory that typically occurs later. That’s a kind of diarrhea for which if you stop the drug and restart therapy, the diarrhea will recur or won’t go away, and that often requires the use of steroids and may require discontinuation of the drug, if the diarrhea continues. Likewise, pneumonitis is also associated with idelalisib.

Idelalisib for Relapsed/Refractory FL

 The patient in this particular situation was someone who had a high FLIPI [Follicular Lymphoma International Prognostic Index] score and a relatively poor expected overall survival from his diagnosis, based on his advanced age and how advanced his disease was. For many patients with follicular lymphoma who fall into the lower FLIPI risk category or have a very good response to their initial line of therapy, their expected overall survival is not that much different from age-matched controls.

While follicular lymphoma is expected to be a disease that is not curable with standard therapy, many patients will have subsequent relapses and be treated and then retreated and retreated again. It is relatively common to now see patients who were treated in the third-line or fourth-line or even later lines of therapy.

When we think about the options available, there are now 3 PI3-kinase inhibitors that are approved in that setting. Idelalisib is one of those. Duvelisib is a second one of those that is approved in that setting. Copanlisib is an IV [intravenous] formulation of a PI3-kinase inhibitor that is also available.

When we think about relapsed and refractory follicular lymphoma, the efficacy of those drugs appears to be more similar than different. The response rates, overall, are in the 40% to 50% range for the majority of those agents, and patients have meaningful progression-free survival. It can be a year or more for the majority of those agents. The distinguishing features stand in terms of the ways the drugs are given. Copanlisib, as mentioned, is an agent that is given via an IV formulation.

Some physicians and patients may consider the IV formulation an advantage in that patients are getting therapy. You know they’re getting therapy when they come in to get their IV medication. For other patients and physicians, they may consider that a disadvantage when they could, instead, be taking a therapy that is administered as an oral agent at home and not need to come back to the physician’s office to get care.

The other thing that we see as a difference between those PI3-kinase inhibitors is the forms, or isoforms of PI3-kinase. Idelalisib is an inhibitor of the PI3-kinase delta. Copanlisib is a pan inhibitor of PI3-kinase, so it affects both the alpha and beta PI3-kinase. Those are ones that have other adverse effects associated with them, so patients need to be monitored closely for hypertension while the drug is being infused and need to be monitored for hyperglycemia, which can cause additional difficulties if the patient has predisposition to diabetes or hyperglycemia for other reasons. The other form of PI3-kinase inhibitor, duvelisib, is more similar in nature to the PI3-kinase delta inhibitor, idelalisib.

PI3K Inhibitors for Relapsed/Refractory FL

 For patients who relapse early after one of those chemoimmunotherapy regimens—bendamustine/rituximab or R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] being the most commonly used ones in the United States—those are patients who have very poor expected overall survival and progression-free survival.

In a landmark paper that was led by Carla Casulo, MD, from the National LymphoCare Study, we saw that patients who received R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] as their frontline regimen and then relapsed within 2 years of their primary therapy had a very poor expected overall survival of approximately 50% or less at 5 years. For those particular patients, we need to think about newer approaches.

There is a chemoimmunotherapy compared with targeted therapy approach being explored in a randomized trial for patients with an early relapse. That is a US intergroup trial looking at the combination of bendamustine/obinutuzumab for those who had R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] as their frontline regimen, or obinutuzumab/CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] for those who had bendamustine as their first-line chemoimmunotherapy regimen. That is 1 arm of the trial. Lenalidomide/obinutuzumab is the second arm of the trial, and a PI3-kinase inhibitor, umbralisib, and obinutuzumab is a third arm in the trial. That really should be the preferred approach for this poor-risk patient population.

For those patients who are unable or unwilling to go on a clinical trial, the kinds of regimens that we might think about in the relapsed setting as approved regimens are bendamustine/obinutuzumab, which this patient got in this particular situation; or lenalidomide and rituximab, which is now approved based on the AUGMENT trial in the relapsed and refractory setting; or other forms of chemoimmunotherapy.

For those patients who are young enough and healthy enough, autologous stem cell transplantation should be considered after that. Those typically would be patients under the age of 70 who are fit and well enough to undergo an autologous stem cell transplantation.

There are also more clinical trials exploring CAR [chimeric antigen receptor] T cells in this setting for patients who have an early relapse.

While this patient experienced an early relapse of follicular lymphoma, which again, happens in about 20% of individuals, the majority of patients will experience a later relapse, something longer than 2 years after initial therapy. For those patients, there are numerous approaches available.

Occasionally, single-agent rituximab can be used in that setting to control disease and help prevent a subsequent relapse. In addition, lenalidomide/rituximab is now approved in that setting. Bendamustine/obinutuzumab is another option, and any other first-line chemoimmunotherapy regimens that weren’t used in the first-line setting are also potential options for use in the second line for a relapse.

For patients who experience a second relapse after that first, early relapse, there are a number of other agents, including those that I just mentioned, that would be options. And additionally, the PI3-kinase inhibitors, by themselves, are approved in this setting.

Christopher R. Flowers, MD | Authors

Articles

Follicular Lymphoma Management: Future Directions

Idelalisib for Relapsed/Refractory FL

PI3K Inhibitors for Relapsed/Refractory FL

Treatment Options for Relapsed Follicular Lymphoma