Indolent Lymphoma: A More Complex Malignancy Than Once Thought

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James O. Armitage, MD, FACP, FRCP

For most patients, relapse is a horrible thing, so I offer maintenance therapy because I know this will increase the time before we need to treat again, if ever. Maintenance keeps patients in remission longer, but we don’t know if it keeps them alive longer.

—James O. Armitage, MD, FACP, FRCP

With a growing number of options for follicular lymphoma, clinicians may wonder whether there is one best regimen. James O. Armitage, MD, FACP, FRCP, Professor of Medicine at the University of Nebraska, Omaha—and Editor-in-Chief of The ASCO Post—tackled this question and offered recommendations at the 2015 Debates and Didactics in Hematology and Oncology in Sea Island, Georgia, an annual conference sponsored by Emory University.

Approach to Treatment

Follicular lymphoma is actually a more complex malignancy than is often believed, according to Dr. Armitage. “It’s becoming increasingly clear that follicular lymphoma is complex and that the relationship between tumor cells and surrounding cells is important.”

Of note, some patients with grade 3 follicular lymphoma have a disease course more like diffuse large B-cell lymphoma. This is important to recognize, because it should dictate a more aggressive treatment, he said. “If you want to cure these patients, you’d better treat them with a [diffuse large B-cell lymphoma]-type regimen,” he recommended, adding that he typically treats all grade 3 follicular lymphomas this way.

The other important question is how aggressively to treat stage I (ie, localized) follicular lymphoma. This early disease will respond well to radiotherapy alone. Studies have uniformly shown that almost half of patients treated with radiotherapy alone are continuously free of disease at 10 years. “Based on this, we usually treat localized follicular lymphoma with involved-field radiotherapy alone,” he said.

A Role for ‘Watch and Wait’?

Given the excellent long-term outcomes with rituximab (Rituxan), is there a place for observation in indolent disease?

The Nebraska Lymphoma Study Group documented the 10-year overall survival rate for patients treated between 1982 and 2000 (ie, before the approval of rituximab) as approximately 50%. This rose to about 75% after the year 2000, he noted.

“Since our current treatment is so good, is it appropriate to watch and wait? Some think not, because of the impact of rituximab on the natural history of lymphoma,” Dr. Armitage noted.

He maintained that observation can be appropriate for patients who are ­asymptomatic and either do not want therapy or are elderly and frail. The caveat is that close monitoring is mandatory; delaying treatment may decrease survival, though this remains unproven, he said.

“You must be willing to observe these patients closely. Seeing them every 6 months is not enough. I see patients monthly at first, then every 3 months at most. If you are going to watch and wait, you cannot ignore these patients!”


There are many active regimens for patients with disseminated follicular ­lymphoma.

“There are patients for whom rituximab alone is reasonable, but for rituximab-containing combinations, which is best?” Dr. Armitage asked.

He discussed as options CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab), CVP-R (cyclophosphamide, vincristine, prednisone, and rituximab), B-R (bendamustine [Treanda] and rituximab), fludarabine-based regimens, and lenalidomide [Revlimid] plus rituximab.

An Italian study compared three regimens and found that complete remission rates were higher for CHOP-R (74%) than for CVP-R (67%) and fludarabine/mitoxantrone/rituximab (72%).1 Progression-free survival at 3.5 years was also longer with CHOP-R (68% vs 52% and 63%, respectively). The PRIMA study showed that CHOP-R produced higher complete remission rates than CVP-R and progression-free survival similar to that associated with FCM-R (fludarabine, cyclophosphamide, mitoxantrone, and rituximab).2

CHOP-R, therefore, is more active than CVP-R, and because of toxicity, fludarabine-based regimens are rarely used in the United States. The bigger question is whether to use CHOP-R or B-R, he said.


The German NHL1 trial appeared to show superiority of B-R over CHOP-R, based on a longer progression-free survival (P = .0281).3 But the results of NHL1 were not substantiated by the U.S.-based BRIGHT trial, which compared B-R to CHOP-R/CVP-R.4 Among the follicular/indolent lymphoma cohort, the complete remission rate with B-R was much lower (27%) than it was in NHL1 (44%).

“When the U.S. group tried to reproduce the NHL1 study, they found no difference in the regimens,” he said.

The toxicity profiles of the two regimens, however, do differ in ways that may be important to patients. There is more vomiting and hypersensitivity reaction with bendamustine but more alopecia and neuropathy with CHOP-R.5 The lack of alopecia with bendamustine has popularized its use, he added.

Comparability between the two regimens was further demonstrated in a matched-pair analysis reported from The University of Texas MD Anderson Cancer Center.6 After six cycles, complete remission rates were 91% with CHOP-R and 93% with B-R; 2-year progression-free survival was 82% and 85%, respectively; and 2-year overall survival was 99% and 94%, respectively. Although the CHOP-R group contained more patients with high-risk criteria, patient outcomes were no worse, he noted.

“I think both of these regimens work, and one regimen is not better than the other. Both are better than CVP-R, and fludarabine is too toxic,” Dr. Armitage concluded.

The New Option: R2

The newest option is rituximab/lenalidomide, the so-called R-squared or R2 regimen. R2 produced a very high complete remission rate (87%) in an MD Anderson series; 93% of evaluable patients became positron-emission tomography (PET)-negative, and the 2-year progression-free survival rate was 89%.7 In a multi-institutional study, the complete remission rate was lower (72%), but 2-year progression-free survival remained high (89%).8 In a 154-patient study, European investigators also reported a lower complete remission rate (36%).9

“As more patients are treated, the results are sometimes not as good as the original report, and this is common,” Dr. Armitage commented. “There has been no comparative trial, but this regimen might offer a similar likelihood to CHOP-R and B-R for keeping low-grade follicular lymphoma patients well.”

Deciding on a Regimen

All things considered, Dr. Armitage weighs the treatment options by asking the following questions: Is the patient fit? How old is the patient? Is the patient symptomatic? What side effects is the patient willing to accept?

Patients who are not generally healthy are more likely to receive rituximab alone. Patients who are ill from cancer are most likely to benefit from CHOP-R or B-R. Elderly patients are more likely to receive B-R than CHOP-R. Side effects should be weighed and patient preferences ­considered.

Optimal Treatment Duration?

Dr. Armitage emphasized that the aim of treatment is to achieve a complete remission. “It’s not okay to just treat the patient for a while and make him feel better. We know there is a huge survival advantage to achieving a complete remission,” he said.

A recent pooled analysis of three trials of patients receiving at least six cycles of chemotherapy plus rituximab confirmed the value of achieving a negative PET/computed tomography (CT) scan after induction.10 The hazard ratios associated with having a positive PET/CT were 3.9 for progression-free survival (P < .0001) and 6.7 for overall survival (P = .0002).

More uncertain is the value of maintenance rituximab in this setting. The PRIMA study “convincingly showed” that maintenance will prolong remission (hazard ratio = 0.50, P < .0001), but it did not demonstrate improved survival.2 The U.S.-based RESORT study, on the other hand, showed no difference in “time to treatment failure” between patients on the maintenance arm and those being observed only. This was defined as progression within 6 months of the last rituximab dose, no response to rituximab retreatment, initiation of alternative therapy, or inability to complete protocol therapy.11

The investigators concluded that intermittent treatment was as effective as maintenance rituximab. In Dr. Armitage’s opinion, the study’s median follow-up of 3.8 years may be too short to determine true differences in outcomes.

“You have to decide how important it is to the patient to be continuously well,” he commented. “For most patients, relapse is a horrible thing, so I offer maintenance therapy because I know this will increase the time before we need to treat again, if ever. Maintenance keeps patients in remission longer, but we don’t know if it keeps them alive longer.” ■

Disclosure: Dr. Armitage reported no potential conflicts of interest.


1. Federico M, Luminari S, Dondi A, et al: R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: Results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol 31:1506-1513, 2013.

2. Salles G, Seymour JF, Offner F, et al: Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): A phase 3, randomized controlled trial. Lancet 377:42-51, 2011.

3. Rummel MJ, Niederle N, Maschmeyer G, et al: Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: An open-label, multicenter, randomized, phase 3 non-inferiority trial. Lancet 381:1203-1210, 2013.

4. Flinn I, van der Jagt R, Kahl B, et al: An open-label, randomized study of bendamustine and rituximab compared with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line treatment of advanced indolent non-Hodgkin’s lymphoma or mantle cell lymphoma: The BRIGHT study. 2012 ASH Annual Meeting. Abstract 902. Presented December 11, 2012.

5. Macdonald D, van der Jagt R, Burke JM, et al: Different safety profiles of first-line bendamustine-rituximab, R-CHOP, and R-CVP in an open-label, randomized study of indolent non-Hodgkin lymphoma and mantle cell lymphoma: The BRIGHT study. 2013 ASCO Annual Meeting. Abstract 8565. Presented May 31, 2013.

6. Phansalkar K, Ahmed M, Fowler N, et al: R-bendamustine vs R-CHOP as initial treatment for advanced stage low grade follicular lymphoma: A matched-pair analysis. 2014 ASH Annual Meeting. Abstract 3048. Presented December 7, 2014.

7. Fowler NH, Neelapu SS, Hagemeister FB, et al: Lenalidomide and rituximab for untreated indolent lymphoma: Final results of a phase II study. 2012 ASH Annual Meeting. Abstract 901. Presented December 11, 2012.

8. Martin P, Jung S, Johnson J, et al: CALGB 50803 (Alliance): A phase II trial of lenalidomide plus rituximab in patients with previously untreated follicular lymphoma. 2014 ASCO Annual Meeting. Abstract 8521. Presented May 30, 2014.

9. Kimby E, Martinelli G, Ostenstad B, et al: Rituximab plus lenalidomide improves the complete remission rate in comparison with rituximab monotherapy in untreated follicular lymphoma patients in need of therapy: Primary endpoint analysis of the randomized phase 2 trial SAKK 35/10. 2014 ASH Annual Meeting. Abstract 799. Presented December 9, 2014.

10. Trotman J, Luminari J, Boussetta S, et al: Prognostic value of PET-CT after first-line therapy in patients with follicular lymphoma: A pooled analysis of central scan review in three multicenter studies. Lancet Haematol 1(1):e17-e27, October 2014.

11. Kahl B, Hong F, Williams ME, et al: Results of Eastern Cooperative Oncology Group protocol E4420 (RESORT): A randomized phase III study comparing two different rituximab dosing strategies for low tumor burden follicular lymphoma. 2011 ASH Annual Meeting. Abstract LBA-6. Presented December 13, 2011.