Kami Maddocks, MD

 I think some of the most important things to recognize when you’re treating patients with follicular lymphoma [LF], number 1, is defining when they present with FL and if they require therapy or not. As I mentioned, treating patients just because they have FL does not improve their survival, but it does expose to them toxicities of therapy. Therefore, making sure that in patients who are asymptomatic with low tumor burden, who do not need treatment, that it’s OK to observe these patients until they meet indications or have symptomatic disease that require treatment. I think ruling out transformed disease is very important in FL, so those patients who present with B symptoms with a very high LDH [lactate dehydrogenase], using the PET [positron emission tomography] scan to determine if there’s an area that has an SUV [standard uptake value] out of proportion to other areas, so that can be biopsied to rule out transformed disease, because these patients, if they have transformed disease, need anthracycline-based therapy.

I think in those patients who do not respond to initial therapy like they should, so not achieving complete remission or they relapse within that 2-year time frame, number 1 again, is reassessing the nature that they don’t have transformation at this time. Because, that has been shown that a certain proportion of those patients will have transformed disease. Then, consideration of referring them for a clinical trial, and just recognizing that those patients have a worse overall survival [OS] than other patients with FL. It’s important to make sure that if there’s a trial available, that they would be able to be treated on thinking about CAR [chimeric antigen receptor] T in some of these early relapse patients and referring them for that. Lastly, as I mentioned that the median OS of FL is over 20 years, so when we’re considering different therapies, it’s also important to think about the toxicities of these therapies in the quality of life for a patient.

Case: A 74-Year-Old Man With Relapsed/Refractory Follicular Lymphoma

A 74-year-old man complains of a 6-month history of fatigue, occasional fevers, decreased appetite, fatigue, and an 8-lb weight loss

PE: palpable right axillary and cervical lymph nodes, palpable ~ 3 cm in both locations; spleen palpable 4.5 cm below left costal margin
 

Labs: ANC 1.6 x 109/L, WBC 11.2 x 109/L, 44% lymphocytes, Hb 9.6 g/dL, plt 98 x 109/L, LDH 315 U/L, B2M 3.5 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, 4% involvement

PET/CT showed enlargement of right axillary, cervical, and mediastinal lymphadenopathy (3.3 cm, 3.1, cm and 4.6 cm respectively)

He was treated with R-CHOP for 6 cycles, achieved complete response and continued rituximab maintenance

24 months later he complained of increasing weight loss, fever and drenching sweats as well as more enduring fatigue and new onset itching; he was currently taking antibiotics for his 3rd bacterial infection in the past year

Repeat PET/CT revealed progression of disease

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

Repeat lymph node biopsy grade 2 follicular lymphoma

12 months later he complained of continued weight loss, increased itching and worsening fatigue; recurrent infections continued

He was started on idelalisib 150 mg PO BID

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Citing clinical pearls from her own experience in working with patients with relapsed/refractory follicular lymphoma, Kami Maddocks, MD, gives advice to colleagues in their efforts to combat follicular lymphoma.

Clinical Pearls in Management of Relapsed/Refractory Follicular Lymphoma

 When we look at the future of follicular lymphoma [FL] and some of the unmet needs, I think 1 of the first things is identifying if we can better decide therapy for patients at initial presentation. As I mentioned, there are prognostic scores, but we don‘t know how to use that to decide treatment. Deciding response and things like maintenance therapies, so minimal residual disease, might be something in the future that we can use to help us to decide if maintenance is appropriate for those patients at high-risk for relapse. Those patients as I mentioned who are at high-risk for death from their FL or have lower overall survival are those patients who relapse within the first 2 years of treatment, and we don‘t know the best treatment for those patients. Although we think maybe using different types of therapy with different mechanism of action in the second-line setting might be more ideal than using chemoimmunotherapy, we don‘t know that and there‘s a large cooperative group trial now trying to see if we can define the best treatment for these high-risk patients.

Chimeric antigen receptor [CAR] T-cell therapy is newly approved for patients with FL after progression after 2 or more prior therapies, but this is also associated with significant toxicities, such as cytokine release and neurotoxicity. I think further defining the right patient population for these, as patients who have gotten very long remissions to their initial 2 therapies probably aren‘t necessarily the most ideal candidates to use this in that setting, but those patients who have done poorly with the initial therapy from the standpoint of not getting into remission or having short time before progression are probably ideal candidates for these therapies. Some of the more promising therapies under development include bispecific therapies, so it‘s targeted CD20 by CD3, these have shown to have good early responses in the B-cell malignancies, including FL, but not the same risk of toxicity with the CRS [cardiorenal syndrome] as the CAR T cells. Other antibody-drug conjugates including those targeting CD [cluster of differentiation]19, and then CD19 antibody therapy is also under investigation for FL.

Kami Maddocks, MD, lists the future directions and unmet needs present in treating relapsed/refractory follicular lymphoma.

Future Directions for Treatment of Relapsed/Refractory Follicular Lymphoma

 The challenges beyond treating patients in the first- and second-line include that patients for every treatment regimen you give them, they typically have less response. So, their remission isn’t as deep, and the treatment doesn’t last as long. Some of the other challenges are what shape the patient’s in, what therapy they’ve had previously, what toxicities of that therapy, and what other comorbidities do they have. I would say that it’s not uncommon to have to give therapies beyond the second-line, so when you see younger patients, even if they get really greater prolonged remissions to their first-line therapy, it’s not uncommon for them to have several relapses. We know that the median overall survival [OS] of a patient with follicular lymphoma [FL] is greater than 20 years, but over that time there are many patients that will require a new treatment off and on. One of the other challenges with treating patients beyond the second-line of therapy is the toxicity. What toxicities have they had with prior therapies and are any of these toxicities lasting? it becomes difficult to retreat with agents that have similar toxicities as prior.

When I’m deciding on a therapy beyond the second-line, I think of the patient’s performance status. How good of shape they are in? What treatments have they had previously? What toxicities have they had to those therapies? What is my goal of treatment? There are several options for therapy beyond the second-line. We know that the options we’ve already discussed such as the different chemoimmunotherapies and lenalidomide can be used if they’ve not been used in the prior 2 lines. PI3K kinase inhibitors are available for third-line and later treatment, or for patients who’ve relapsed after 2 therapies. We have 4 PI3 kinase available, 3 in this setting and then 1 after 3 or more prior therapies. Idelalisib is an oral PI3K kinase inhibitor, duvelisib is another oral PI3K kinase inhibitor, and copanlisib is a BPI3P - PI3 kinase inhibitor all available. Tazemetostat is an EZH2 inhibitor available for relapsed [R/R] FL in this setting, and most recently, we’ve seen the approval of chimeric antigen receptor T-cell or CAR T-cell therapy in this setting. Although, the use of that I think must be thought out regarding which of your patient… because of the toxicities, if a patient is a candidate for that therapy and where that therapy should be used.

When deciding therapy in both second-line and in third-line, I think it’s also important to look at what the patients have had for their other therapies and their responses to those therapies. We know in a patient like this, who had 2 regimens of chemoimmunotherapy and did not have long remission durations to those therapies, that we often think about using a different type of therapy. Therefore, even in this second-line in this patient, this is a patient I might have considered using something different than chemoimmunotherapy, something with a different mechanism of action, so this is when we think about using the immunomodulator, lenalidomide in the second-line, or when we think about using the PI3K inhibitors in the third-line setting because we know that this patient seems like he’ll respond to chemotherapy, but not get prolonged remissions from chemotherapy.

Therefore, using something that targets the disease in a different way is attractive in a patient like this in the second- and third-line setting. When you look at the different PI3K inhibitors, they have similar overall response rates and progression-free survival [PFS]. To me, there’s no right or wrong 1 to choose in any clinical setting. Their toxicities are a little bit different, and again 2 are oral and 1 is IV [intravenous] that are approved in this setting. You must look at a patient and their comorbidities and what your goals are with the patient in deciding which PI3K kinase inhibitor might fit that patient appropriately. There is some data with both the idelalisib and copanlisib, where they evaluated patients who had progressed within that 2-year time frame, which I’ve said is a higher risk FL patient, which we know has a worse overall outcome. Both of those have been evaluated in that patient population and are shown to have similar responses in PFS in those patients who are considered high-risk by short time to relapse, as in those patients who achieve prolonged remissions with their IV therapy.

The challenges faced in treating patients beyond second-line treatment are addressed. Kami Maddocks, MD, reviews the frequency of patients who require third- and fourth-line treatment, in addition to the factors that affect treatment decisions in later lines of therapy.

Treatment Challenges Beyond Second-Line in Relapsed/Refractory Follicular Lymphoma

: When choosing a second-line therapy for patients with follicular lymphoma [FL], there‘s a number of options. Decisions should be based on what therapy did the patient receive in first-line? Did they receive R-CHOP [rituximab, cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (oncovin), prednisolone]? Did they receive BR [bendamustine plus rituximab]? Did the receive single agent rituximab? How did they tolerate that therapy? How long did their response to that therapy last? There‘s always an option to repeat the use of chemoimmunotherapy. So, if somebody had BR or R-CHOP in the front line, and they get a prolonged response to chemotherapy, you could consider using the other chemoimmunotherapy option at relapse.

Again, a lot of times my preference is to save R-CHOP. Therefore, if somebody is going to transform, I have that anthracycline based therapy. But again, with a good response to chemoimmunotherapy, you can use a different chemoimmunotherapy rituximab in combination with lenalidomide is an option for second line therapy, and this is probably my most used second-line treatment. I feel like this is a good option in both patients who‘ve had a good response to first-line therapy and those patients who have a little bit earlier of a relapse changing the antibodies, so obinutuzumab as I mentioned, this can be used in frontline follicular lymphoma. Although, typically this is something I use in combination with either chemotherapy or consider it in combination with lenalidomide therapy when patients relapse. I do not use maintenance therapy in the second-line setting.

Considerations for subsequent treatment options in the second-line setting for patients with follicular lymphoma are reviewed by an expert hematologist.

Kami Maddocks, MD | Authors

Articles

Clinical Pearls in Management of Relapsed/Refractory Follicular Lymphoma

Future Directions for Treatment of Relapsed/Refractory Follicular Lymphoma

Treatment Challenges Beyond Second-Line in Relapsed/Refractory Follicular Lymphoma

Options for Second-Line Therapy in Patients With Follicular Lymphoma