Cheson Considers the Most Effective Therapeutic Strategies for Patients With Follicular Lymphoma

Bruce D. Cheson, MD

Bruce D. Cheson, MD

Bruce D. Cheson, MD, recently shared the treatment options and decisions he makes when treating patients with follicular lymphoma. Cheson, deputy chief, Division of Hematology/Oncology, Department of Medicine, MedStar Georgetown University Hospital, explained his treatment decisions based on 2 case scenarios during aTargeted Oncologylive case-based peer perspective presentation.

Case 1

August 2014

A 70-year-old man presented to physician complaining of fatigue lasting several months, a recent weight loss of 15 pounds, and a mass on right side of the neck. His past medical history (PMH) was remarkable for gastrointestinal reflux, which he controlled with proton pump inhibitors, and obstructive sleep apnea. A physical exam (PE) showed a right supraclavicular lymph node (7 cm) and his spleen was palpable (5 cm below the costal margin). His ECOG performance status (PS) was 1.

Laboratory findings showed leukocytes at 3.21 x 10⁹/L, platelets at 99 x 10⁹/L, lactate dehydrogenase (LDH) at 302 U/L, and hemoglobin (Hb) levels at 9.9 g/dL. Levels of aspartate aminotransferase were noted at 162 U/L and alanine transaminase at 201 U/L.

An excisional biopsy of the right supraclavicular node showed CD10+, Bcl2+, CD5— with immunohistochemistry (IHC) staining. Bone marrow showed paratrabecular infiltration by small cleaved lymphocytes. A PET-CT showed enlargement of the right supraclavicular lymph node (3 x 7 cm) and 3 mediastinal lymph nodes (3.2, 3.5, and 4.4 cm); diffusely enlarged nodes were found in the retroperitoneal, mesentery, and inguinal regions.

TARGETED ONCOLOGY: What is the prognosis of this patient?

Cheson:When we evaluate a patient with follicular lymphoma, we categorize them on the basis of the Follicular Lymphoma International Prognostic Index [FLIPI], including the number of nodal sites, LDH stage, and Hb levels.

This patient is greater than 60 years, so he gets a point for that; he has greater than 4 nodal sites, which means another point; elevated LDH, another point; low Hb and advanced stage, each of which gives him another point. Thus, he has 5 points, which puts him at high risk. With conventional chemoimmunotherapy, his 10-year overall survival [OS] is approximately 35%.

TARGETED ONCOLOGY: Does this patient require treatment?

Cheson:When we decide on treatment for patients with follicular lymphoma, we consider their age, PS, and comorbidities. There are several relatively conventional choices that are available. In my opinion, the currently preferred initial therapy is the combination of bendamustine (Treanda)and rituximab (Rituxan; BR). Another option is rituximab and CHOP (cyclophosphamide, doxorubicin [Adriamycin], vincristine [Oncovin], and prednisolone; R-CHOP). A less desirable option would be rituximab, cyclophosphamide, vincristine, and prednisolone, which in multiple randomized trials is inferior to the other 2.

Some physicians do use monotherapy with rituximab in patients who have low-volume disease or are relatively asymptomatic; however, I find that the response rate is fairly low and the durability reasonably short. I would only consider it in patients who are elderly and frail and have other comorbidities. Bendamustine and rituximab is my preferred treatment.

A recent study called the GALLIUM trial compared rituximab and chemotherapy versus chemotherapy combined with the next-generation anti-CD20 monoclonal antibody, obinutuzumab (Gazyva).¹In this very large randomized trial, there was a modest progression-free survival (PFS) benefit in favor of the obinutuzumab therapy, but without a survival benefit and with increased toxicity. If this regimen, chemotherapy plus obinutuzumab, is approved by the FDA, then it will be left up to the physician’s choice whether the modest benefit outweighs the greater toxicity and lack of survival advantage.

The patient was treated by the local oncologist with R-CHOP for 6 cycles. Post treatment, he achieved a partial metabolic response.

TARGETED ONCOLOGY: Do you agree with the decision to treat with R-CHOP?

Cheson:As I mentioned previously, I feel that bendamustine plus rituximab is the preferred regimen to R-CHOP. This conclusion is based on safety and, in 1 randomized trial, efficacy as well.

TARGETED ONCOLOGY: Should the patient receive maintenance therapy?

Cheson:Now the question arises regarding the role of maintenance therapy following the induction chemoimmunotherapy. There have been at least 6 randomized trials looking at this question. There have been 3 trials with rituximab alone as induction therapy followed by maintenance. Additionally, there have been 2 trials with chemoimmunotherapy followed by rituximab maintenance, including the 10-year follow-up data of the very large PRIMA study.²None of these studies have shown a survival benefit associated with maintenance therapy.

At the recent American Society of Hematology annual meeting, Rummel and coworkers presented data also showing a lack of a survival benefit for maintenance rituximab after BR therapy.³Since maintenance is associated with increased expense, toxicity, and nuisance, without any survival benefit, I do not recommend maintenance therapy for patients with follicular lymphoma in the frontline setting.

July 2016

After 23 months, the patient complained of returning symptoms.A PET revealed enlargement of the affected mediastinal nodes and the maximum standardized uptake values (SUVmax) of all nodes was 12.A repeat CT revealed progression of disease.

TARGETED ONCOLOGY: What are the choices for therapy at this point?

Cheson:This patient relapsed within 2 years of his initial treatment. Several groups have now demonstrated that progression of disease at 24 months makes the patient at risk for poor outcome. Patients who do not progress within 2 years have an OS consistent with an age-matched population without lymphoma. However, those who progress within 2 years have a long-term survival in the range of 30% to 40% and, therefore, are an unmet medical need.

This patient would fall into the category of an early relapse and a patient who is rituximab-refractory. There are a couple of potential treatments. The first is the combination of bendamustine and alemtuzumab. We have published data on this regimen and it demonstrated with rituximab-refractory patients, compared with bendamustine alone, that there is not only a prolongation of PFS, but also an improvement in OS. The treatment of bendamustine and alemtuzumab followed by 2 years of alemtuzumab maintenance, since it does prolong survival, would be a recommended therapy and is approved by the FDA.

Other treatments for patients like this include stem cell transplant and radioimmunotherapy, which is rarely used anymore. In each of these lines of therapy, the preferred treatment is always a clinical trial.

The patient was started on bendamustine plus obinutuzumab for 6 cycles with a plan for obinutuzumab maintenance.He achieved a partial response (PR) after completing induction therapy.

February 2018

Sixteen months later, the patient reported feeling tired, but could resume most normal activities. His ECOG PS was now a 1. A PET scan with diagnostic CT showed diffuse¹⁸F-FDG uptake in multiple lymph nodes and in the spleen. The largest involved nodes were the right supraclavicular (6.2 cm), left mesenteric (4.8 cm), and splenic hilar (2.7 cm) nodes.

A repeat lymph node biopsy showed grade 2 follicular lymphoma and the patient was started on copanlisib (Aliqopa) and subsequently developed grade 3 diarrhea. After 3 months, the patient developed a PR with>50% reduction in lymphadenopathy in all involved nodes.

TARGETED ONCOLOGY: What would you do at this point?

Cheson:Unfortunately, he had a PR to therapy and now he is a third-line patient. Standard chemoimmunotherapy is generally not used in this context. One thing you need to do is make sure that he has not transformed, so a PET/CT scan should be considered. If there is a node that has a suspiciously high standardized uptake value, it should be biopsied to make sure a transformation has not occurred.

If transformation hasn’t occurred, there are a couple of drugs that are active in this setting. The first of them is idelalisib (Zydelig), a PI3 kinase inhibitor, which achieves a response rate of around 54%, mostly PRs, with a median PFS of around 11.2 months. More recently copanlisib, another PI3 kinase inhibitor, has been approved by the FDA. Idelalisib is specific to the delta isoform, whereas copanlisib targets the alpha and delta isoforms. It has a similar complete and overall response rate and PFS. Its benefit is that it has considerably less toxicity than idelalisib in the way of less colitis, pneumonitis, transaminitis, and rash; however, it has unique adverse effects. Those are hyperglycemia and hypertension, but they are transient and generally do not translate into any clinically detrimental effects.

A lot of physicians, I am told, use ibrutinib (Imbruvica), a Bruton’s tyrosine kinase inhibitor, in this setting; however, in the study that we performed, it is associated with a response rate of only 20.9%, of relatively short duration. Therefore, it is not recommended in this context.

After 3 months, the patient developed a partial remission with>50% reduction in lymphadenopathy in all involved nodes.

TARGETED ONCOLOGY: What would you do after the patient develops a partial remission?

Cheson:Copanlisib is administered weekly intravenously for 3 weeks out of 4 indefinitely as long as the patient responds and tolerates the drug. Therefore, I would keep the patient on copanlisib until 1 of those 2 endpoints occurred, either he developed adverse effects or the disease started to progress.

Case 2

January 2015

A 65-year-old woman presented to her primary care physician complaining of sweats and swelling in the neck. Her PMH was remarkable for osteoporosis and neurogenic bladder. A PE showed an enlarged spleen 2 cm below costal margin and bilateral cervical and axillary lymphadenopathy. She had an ECOG PS of 0.

Laboratory findings showed a white blood cell count at 12 x 10⁹/L with 45% lymphocytes and platelet count at 213 x 10⁹/L. Hb levels rose to 11.5 g/dL and LDH to 212 D/L.

An excisional biopsy of lymph nodes showed CD10+ and BCL2+ with IHC, and the patient was diagnosed with follicular lymphoma, grade 3a. Additionally, a bone marrow biopsy showed 40% of the cells were involved and a¹⁸FDG-PET showed SUVmax of 9 with discrete masses bilaterally in the cervical and axillary region and increased uptake in the liver.

TARGETED ONCOLOGY: How would you stage her?

Cheson:On the basis of bone marrow involvement, this woman would be stage IV follicular lymphoma. Based on her age, the number of nodal sites, anemia, and advanced stage, even with a normal LDH, she would have 5 points [based on the FLIPI score], making her a high risk. Again, her 10-year projected survival would be about 35%.

One must recognize that the FLIPI score was developed prior to the use of rituximab. The FLIPI-2 score was developed subsequent to that, but it was still prior to the widespread availability of bendamustine and of some of the newer targeted drugs, such as idelalisib and copanlisib. So how relevant these [scores] are, in the context of current treatments, remains to be demonstrated.

TARGETED ONCOLOGY: Does this patient require treatment and, if so, what are those treatment options?

Cheson:I do think she requires treatment, because she is experiencing disease-related symptoms and is already becoming anemic. In this woman, I would still administer BR therapy. It is better tolerated, particularly in older patients, over R-CHOP, and I would not use maintenance therapy. Her particular comorbidities do not factor into the equation. Osteoporosis and neurogenic bladder are really of no significance in determining treatment.

The follicular lymphomas are graded based on the number of large cells or central blasts, and how they are among the central sites or small cleaved cells. Grades 1, 2, and 3a basically have the same outcome in most studies; 3b, on the other hand, has sheets of large cells. Its outcome is more consistent with diffuse large B-cell lymphoma and should be treated as such with R-CHOP.

The patient was started on bendamustine plus rituximab for 6 cycles and achieved a PR with a 75% reduction in tumor volume.

TARGETED ONCOLOGY: What are your thoughts on subcutaneous rituximab (Hycela)?

Cheson:Subcutaneous rituximab is now available. The published data clearly demonstrate comparable pharmacodynamics with intravenous rituximab. A similar response rate was also demonstrated, while also being well tolerated. We should remember that the first dose, even if you get subcutaneous rituximab, is intravenous just like standard rituximab. It is the subsequent doses that are subcutaneous; they take about 7 to 10 minutes to administer, and generally all that is noted is a transient local reaction.

In the published data, not only was the efficacy evaluated in some patients, but also preference and quality of life. Both of these factors are greatly in favor of the subcutaneous rituximab. The only issue with this agent is the economic one; a number of hospitals are concerned about the fact that patient time in the chair is considerably less with subcutaneous. Therefore, the concern is that there will be less money [coming in] with this drug.

TARGETED ONCOLOGY: Will you use biosimilar rituximab if it becomes available?

Cheson:There are number of biosimilars of rituximab that are in development. Since they are biosimilars, they are not only bio but they are similar in their efficacy and toxicity. If there are differences in their efficacy or toxicity, they cannot be considered a biosimilar. Rituximab is ingrained into how we treat B-cell malignancies. For a biosimilar to make a dent, it would have to be considerably less expensive than rituximab. I don’t think 10%, 15%, or 20% will cut it, but if it is 25% or 30% or more, it might provide a challenge to intravenous rituximab. For patient preference, I still think that subcutaneous rituximab would be preferred.

January 2017

After 32 months, the patient complained of her symptoms returning and a follow-up CT showed disease progression in the axillary and hilar lymph nodes and a PET showed a SUV of 11. The patient had a repeat biopsy of a lymph node, which was consistent with follicular lymphoma grade 3a.

TARGETED ONCOLOGY: What are the options for treatment after the progression of disease?

Cheson:At this point, there are a number of options for treatment. Ibritumomab tiuxetan (Zevalin), a radioimmunotherapy, is very effective but rarely used these days because of concerns with secondary leukemias. Single-agent bendamustine, another option, is rarely used and, in this case, the patient already received bendamustine. Bendamustine/obinutuzumab is another option. In the GADOLIN trial, which resulted in the FDA approval for this regimen, only 3 patients had received prior bendamustine.⁴So we don’t know how efficacious this combination would be in a woman such as this. Another treatment option is stem cell transplant, but this patient is a bit on the older side.

Clinical trial is always the answer because that is how we get these drugs approved by the FDA. That is how we got rituximab, bendamustine, idelalisib, and copanlisib approved. We put patients on clinical trials, demonstrated their efficacy and safety, and provided new and improve therapeutic options for our patients.

The patient was referred to an academic center for treatment. She was enrolled in an open-label clinical trial of lenalidomide (Revlimid)/rituximab for 12 cycles and achieved stable disease after 3 months.

TARGETED ONCOLOGY: Should she receive maintenance therapy?

Cheson:In this situation, following rituximab/lenalidomide, the so-called R²regimen, the question of maintenance is being addressed in a randomized clinical trial—the results of which we do not yet have. If there are data eventually that show a benefit for maintenance in this context, then I would use it. If, like almost every other study, except for the GADOLIN trial, maintenance isn’t associated with a survival benefit, then I would not recommend it.

January 2018

A year later, the patient presented with low-grade fever and chills, but she otherwise appeared well and was continuing to exercise regularly with an ECOG PS of 0. A PET-CT showed further progression in the axillary lymph nodes.

TARGETED ONCOLOGY: What are the choices for treating this patient after progression on 2 lines of therapy?

Cheson:The choices for treating this patient that are approved by the FDA include the yttrium-90 ibritumomab tiuxetan, but the way we treat patients currently would be with a PI3 kinase inhibitor. The 2 of them on the market are idelalisib and copanlisib. There are striking differences between the 2 once you get past the similar response rates and similar PFS, particularly surrounding administration. Idelalisib is an indefinite oral drug twice a day in the form of a pill. Copanlisib is intravenous weekly for 3 weeks and a week off, indefinitely. The toxicity profiles are strikingly different. Idelalisib is associated with colitis, pneumonitis, rash, and transaminitis, whereas copanlisib has a much lower likelihood of those effects, but does induce transient and reversible hyperglycemia and hypertension.

It is a discussion that you need to have with your patient: oral versus intravenous, the toxicity, you have to give antibiotic prophylaxis antimicrobials with idelalisib and, concurrently with copanlisib, it is not as clear that you need to give those drugs. This is because idelalisib has been associated with an increased risk of opportunistic infections, including pneumonitis and others, which are much less common in association with copanlisib.

TARGETED ONCOLOGY: What is the role for transplant in this setting?

Cheson:The role of transplant is controversial. In fact, in follicular lymphoma, if you look at data from the national LymphoCare study, which was a database of thousands of patients, the number of patients in this setting that were referred to transplant was less than 2%.⁵It also becomes a question of what kind of transplant. If a patient has had multiple prior lines of therapy, an autotransplant is of no use. It has only been suggested to be useful in patients with very minimal disease, if any, and minimal prior therapy. As far as allogenic transplants, the data to support them are mostly registry data, which have issues in their interpretation with selection bias particularly as to who gets transplant and who doesn’t.

To conclude, we rarely do transplant and there are other therapies coming along, such as chimeric antigen receptor T-cell therapy, which I would prefer to refer patients for, rather than sending them for a stem cell transplant. Once again, there are new drugs being developed all the time for follicular lymphoma that, hopefully, will continue us on our way to a chemo-free world with safer and more effective strategies for avoiding cytotoxic therapies.

References:

1. Shah NN, Stetler-Stevenson M, Yuan CM, et al. Minimal residual disease negative complete remissions following anti-CD22 chimeric antigen receptor (CAR) in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL). Presented at: American Society of Hematology 58th Annual Meeting & Exposition; December 2-6, 2016; San Diego, CA. Abstract 650.
2. Salles GA, Catalano J, Feugier P, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial.Lancet. 2011;377(9759):42-51. doi: 10.1016/S0140-6736(10)62175-7.
3. Rummel MJ, Buske C, Hertenstein B, et al. Four versus two years of rituximab maintenance (R-maintenance) following bendamustine plus rituximab (B-R): initial results of a prospective, randomized multicenter phase 3 study in first-line follicular lymphoma (the StiL NHL7-2008 MAINTAIN study). Presented at: American Society of Hematology 59th Annual Meeting & Exposition; December 9-12, 2017; Atlanta, GA. Abstract 48
4. Sehn LH, Chua N, Mayer J, et al. GADOLIN: primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma.J Clin Oncol.2015;33(suppl 18; abstr LBA8502). meetinglibrary.asco.org/record/110467/abstract.
5. Friedberg JW, Taylor MD, Cerhan JR, et al. Follicular lymphoma in the United States: first report of the national LymphoCare study.J Clin Oncol.2009;27(8):1202-1208. doi: 10.1200/JCO.2008.18.1495.