Doctors Debate: Should Asymptomatic Patients With Follicular Lymphoma Be Actively Monitored With Watch-and-Wait Strategy or Immediately Treated?

Jean Louise Koff, MD, MS

Two options exist for initial treatment of patients with asymptomatic advanced follicular lymphoma (FL): the watch-and-wait approach or immediate therapy. Research findings show that either approach can lead to overall survival (OS) benefits, but there may be a difference in progression-free survival (PFS) and the impact of adverse effects (AEs).

James O. Armitage, MD

The question of whether patients with asymptomatic advanced-stage FL should undergo watch-and-wait observation or start treatment immediately was addressed at the 2020 Debates and Didactics in Hematology and Oncology meeting hosted by Winship Cancer Institute of Emory University in Atlanta, Georgia. During the debate, Winship’s Jean Louise Koff, MD, MS, assistant professor of hematology and medical oncology at Emory School of Medicine, argued for watching and waiting, and James O. Armitage, MD, professor of medicine at University of Nebraska Medical Center in Omaha, supported immediate treatment.

The Case for Watch and Wait

Traditional treatment for advanced-stage FL consisted of administering purine analogues and chemotherapy, which had an 18.5-year median OS duration among patients with low-grade disease.¹ Later, immunochemotherapy with rituximab (Rituxan) improved outcomes with an OS of 5 years in more than 90% of patients.² The data supporting a watch-and-wait approach in asymptomatic FL patients with advanced stage and low tumor burden date back 40 years, Koff said.

Aside from chemotherapy and radiation alone, the treatment options for FL consist of rituximab/chemotherapy regimens such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); rituximab added to cyclophosphamide, vincristine, and prednisone (R-CVP); and rituximab plus lenalidomide (Revlimid), according to the Lymphoma Research Foundation.³ However, clinicians may also choose to treat their patients with FL by a method of watch and wait, or observation, for those with indolent disease.

“About 40 years of research has shown that watch and wait for asymptomatic, low tumor burden FL is a very reasonable approach for most patients. There is plenty of data showing that overall survival is not improved with early treatment. When we treat early for these patients, thee is an improvement in PFS, but many patients who go on watch and wait have [equally] good outcomes after treatment when they eventually progress to high tumor burdens,” Koff told Targeted Therapies in Oncology (TTO) in an interview. “There are certainly instances where treatment for asymptomatic FL may be advisable, and a lot of those instances have to do with patients’ preference, because many patients can have anxiety related to the watch-and-wait approach, even though the data suggest overall survival would not be negatively [affected].”

Watch and Wait Versus Rituximab

As the basis for her argument, Koff described an open-label phase 3 study of patients from 118 centers in the United Kingdom, Australia, New Zealand, Turkey, and Poland (NCT00112931). Randomization was initially performed 1:1:1 in 3 arms: rituximab induction (n = 84), rituximab maintenance (n = 85), and watch and wait (n = 83). The rituximab induction arm was stopped early, and additional patients were recruited to the remaining 2 study groups. In total, 379 patients were randomized to receive maintenance rituximab (n = 192) or watch and wait (n = 187). The coprimary end points being assessed in the study were the time to start of new treatment and quality of life (QOL) at month 7.⁴

In the induction arm, rituximab 375 mg/m² was administered weekly for 4 weeks. In the maintenance arm, patients received the 375 mg/m² dose weekly for 4 weeks, followed by rituximab infusions every 2 months for 2 years. All patients in the trial were 18 years or older and had previously untreated grade 1 to 3a disease, stage II to IV, with low tumor burden and an ECOG performance status of 0 to 1.

The HR for the time to new treatment in the rituximab maintenance arm versus the watch-and-wait arm was 0.21 (95% CI, 0.14-0.31; P < .0001). Specifically, 46% of patients in the watch-and-wait arm did not require treatment at 3 years versus 88% in the maintenance rituximab arm.

In addition, Koff noted that although 3-year PFS among patients who were observed rather than treated was much lower at 36% compared with 82% with maintenance rituximab (HR, 0.23; 95% CI, 0.16-0.32; P = .0001), the OS was similar between the 2 arms (HR, 0.73; 95% CI, 0.34-1.54; P = .40). The time to transformation was also similar (HR, 0.62; 95% CI, 0.31-1.26; P = .19).

Among those who received rituximab induction, 78% (95% CI, 69%-87%) did not need treatment at 3 years. Notably, rituximab induction was not found to improve QOL in patients compared with watch and wait.

Watch and Wait Versus Rituximab/Chemotherapy

The National Lymphocare Study (NCT00097565), an observational study, compared the watch-and-wait approach with rituximab plus chemotherapy or rituximab monotherapy in 1754 patients with newly diagnosed stage II to IV FL. To manage the disease, 386 patients (22%) were assigned to watch and wait and 296 (17%) received rituximab monotherapy. The remaining 1072 patients (61%) were enrolled into the chemoimmunotherapy arm and received either R-CHOP, R-CVP, or rituximab with a fludarabine-based combination.⁵

“There’s never been a randomized trial comparing R [rituximab]–chemotherapy to the watch-and-wait approach,” Koff said while discussing the study data. “R-chemotherapy is not typically what we would recommend for patients with low tumor burden. The large National Lymphocare Study looked at real-world practices and then used propensity score matching to compare agents that had similar indications for either watch and wait or initiation therapy. Then outcomes were compared, which were stratified by what approach the patient received. Unsurprisingly, the OS outcomes were similar between those 2 groups.”

The study revealed no significant difference in terms of OS between watch and wait and rituximab monotherapy (HR, 0.74; 95% CI, 0.51-1.08), nor was there a significant difference watch and wait compared with rituximab plus chemotherapy (HR, 0.77; 95% CI, 0.55-1.08).

Considering All Options

Considerations for choosing the watch-and-wait approach versus initiating treatment, Koff said, involve reflecting on the toxicities of anti-CD20 therapy and the implications of treating patients with advanced disease during the coronavirus disease 2019 (COVID-19) pandemic.

“With any agent, there is a risk of toxicity. When you’re considering single-agent rituximab therapy, it is relatively well tolerated. One of the common adverse effects is infusion reaction, which is fairly manageable. There are some longer-term toxicities in some patients, such as, where you can have a low level of immune cell suppression or B-cell aplasia,” Koff explained. “Another toxicity to consider is financial toxicity, which, of course, you are not going to see with the watch-and-wait approach.”

Koff continued: “In this time of the COVID-19 pandemic, it’s important to consider patients’ exposure to other people, which would be less likely with a watch-and-wait telemedicine visit than it would for patients who have to come into the clinic for an infusion.”

When asked how she would move forward with a patient who has advanced-stage symptomatic FL, Koff replied, “There are many considerations for frontline treatment. Much of it has to do with individual patient-level factors. For a patient who is symptomatic, we would look at the degree of tumor burden and comorbidities, and we would talk to the patient about their preferences. Because there is no standard of care for FL, we would evaluate whether the patient meets the criteria for a clinical trial. There’s no one-size-fits-all [approach] with new treatment of a patient with FL.”

The main takeaway from Koff’s argument was that studies have demonstrated that both watch and wait and immediate treatment are feasible in advanced FL. A phase 3 trial (JCOG 1411, FLORA) is exploring watch and wait versus rituximab in frontline treatment of patients with advanced-stage FL with low tumor burden. In a pool of 290 patients in Japan, the study will assess event-free survival as its primary end point, along with secondary end points of OS, PFS, chemoradiotherapy-free survival, transformation-free survival, and AEs.⁶

The Case for Immediate Treatment

For patients with asymptomatic low-grade FL who have a high tumor burden, Armitage considers immediate treatment to be reasonable option. However, he stated that he is not against the latter strategy.

“Watch and wait is a reasonable approach for some patients, but it’s also true that treatment with R-CHOP or another high-quality regimen leads to cure in some patients. That’s something for both oncologists and their patients to take into consideration,” Armitage told TTO in an interview.

In his presentation, Armitage noted other factors oncologists should consider: whether a patient has localized disease versus disseminated disease, the patient’s age, presence of any comorbidities, the potential for cure with immediate treatment, and the patient’s personal preference.

“For patients with localized FL, we have known that radiotherapy can be curative, and that’s what most physicians would recommend if it can be administered safely. When you see a patient with newly diagnosed FL, you need to know if they have low-grade or high-grade [disease]. The latter is more like diffuse large B-cell lymphoma, or they might have areas of diffuse large B-cell lymphoma mixed in with a low-grade FL. In both of these instances, immediate treatment would be reasonable thing to do. In some patients the diagnosis of transformation to DLBCL might be made by evaluation of an elevated lactate dehydrogenase level or a very high standardized uptake value a PET scan.” Armitage said.

Does Watch and Wait Compromise OS?

The data Armitage mentioned came from a retrospective study that evaluated 43 patients with grade 1 or 2 FL who were monitored with the watch-and-wait approach. The coprimary end points of the study were time to treatment and OS. The results showed that 63% of patients who were observed through watch and wait had not been treated at a median of 86 months of follow-up. The 10-year OS rate in that arm was 85%.⁷

In another cohort of patients who had either watch and wait or chlorambucil, 19% of patients were untreated at 10 years, and the 10-year survival rate was 64%.

Revisiting the same data from the phase 3 trial Koff presented earlier, investigating rituximab induction and maintenance versus watch and wait, Armitage noted that no difference in OS was observed with watch and wait versus rituximab maintenance (94% vs 97%).⁴

Choosing the Right Course

The key consideration for a patients with disseminated, low-grade FL should be the ability to get them to cure, Armitage stated, and this was backed up with evidence from a randomized controlled trial of watch and wait versus immediate treatment with chlorambucil,which assessed OS and relapse-free survival as its coprimary end points. A total of 309 patients were enrolled, and all patients were randomized in the study.⁸

OS was found to be similar in both study arms. At 5 years, the OR rates was 57% (95 % CI, 49%-64%). At 10 years, the OS rates were calculated as 35% (28%-43%), and he 15-years OS rates were 21% (95% CI, 16%-29%). The median OS observed in the immediate treatment arm was 5.9 years (range, 0-17.8 years) compared with 6.7 years (range, 0.5-18.9 years) in the watch and wait arm. Armitage noted that based on these data, patients are unlikely to ever relapse.

The Future of Immediate Treatment Versus Watch and Wait

Regarding the appropriate approach for patients with asymptomatic FL with high tumor burden, Armitage believes it would be important to identify patients who are likely to progress early. Currently, no test can predict how disease will progress without immediate treatment. “If we had a test to know which patients are the ones that are going to progress early, with or without treatment, that would be helpful. We don’t have a test to tell who’s going to do that right now,” he said.

Koff agreed but still favored nontreatment. “We need a biomarker for detecting who that population is and what predisposes them towards better outcomes. Before we apply early treatment to the broader FL population, we need to have better markers for identifying those patients who may be cured before we expose them to therapy when watch and wait is just as good,” she said.

The idea of a biomarker is the 1 thing standing in the way of oncologists being absolutely sure about immediate treatment over the watch-and-wait approach.

Room for Both Options in the FL Paradigm

The question of whether to initiate treatment right away or watch and wait for signs of a need for therapy in patients with asymptomatic advanced-stage FL has no certain answer. Notably, Koff and Armitage did not disagree on most points made during their debate. Both stated that there is a place for watch and wait and for immediate treatment. The trick is for oncologists to understand the factors that can lead to the best decision for each patient, but both Koff and Armitage said they await results from this area of active research.

_Reference:

_{1. Tan D, Horning SJ, Hoppe RT, et al. Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: the Stanford University experience. Blood. 2013;122(6):981-987. doi:10.1182/blood-2013-03-491514}

_{2. Nastoupil LJ, Sinha R, Byrtek M, et al. Outcomes following watchful waiting for stage II-IV follicular lymphoma patients in the modern era. Br J Haematol. 2016;172(5):724-734. doi:10.1111/bjh.13895}

_{3. Getting the facts: follicular lymphoma. Lymphoma Research Foundation. Updated February 2018. Accessed August 24, 2020. https://bit.ly/3aR1RkR}

_{4. Ardeshna KM, Qian W, Smith P, et al. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol. 2014;15(4):424-435. doi:10.1016/S1470-2045(14)70027-0}

_{5. Casulo C, Byrtek M, Dawson KL, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study. J Clin Oncol. 2015;33(23):2516-2522. doi:10.1200/JCO.2014.59.7534. Published correction appears in J Clin Oncol. 34(12):1430.}

_{6. Miyamoto K, Fukuhara N, Maruyama D, et al; Lymphoma Study Group of the Japan Clinical Oncology Group. Phase III study of watchful waiting vs. rituximab as first-line treatment in advanced stage follicular lymphoma with low tumour burden (JCOG1411, FLORA study). Jpn J Clin Oncol. 2018;48(8):777-780. doi:10.1093/jjco/hyy085}

_{7. Advani R, Rosenberg SA, Horning SJ. Stage I and II follicular non-Hodgkin’s lymphoma: long-term follow-up of no initial therapy. 2004;22(8):1451-1459. doi:10.1200/JCO.2004.10.086}

_{8. Ardeshna KM, Smith P, Norton A, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet. 2003;362(9383):516-522. doi: 10.1016/S0140-6736(03)14110-4}