Follicular Lymphoma: Is the Road to Cure Paved With Gallium?

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The roadside along the path to curing follicular lymphoma is riddled with the debris of failed cytotoxic regimens. For decades, clinical trials unsuccessfully pitted various chemotherapy combinations against each other. It took but a single, noncytotoxic molecule, rituximab (Rituxan), to forever alter the landscape. Regardless of the chemotherapy with which it was combined, survival was prolonged with minimal additional adverse effects.1-3

Unfortunately, the next few years once again focused on anointing the optimal chemotherapy—this time to partner with rituximab. The Italian FOLL05 study concluded that R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone) was superior to R-FN (rituximab plus fludarabine, mitoxantrone) in terms of toxicity and to R-CVP (rituximab plus cyclophosphamide, vincristine, prednisone) in terms of efficacy.4 The German STIL study5 and the BRIGHT trial established bendamustine as a reasonable alternative to multiagent regimens based on efficacy and safety.6,7 As a result, this alkylating agent combined with rituximab (BR) has assumed the position of the most widely used front-line regimen.

Regardless of the chemoimmunotherapy regimen, the progression-free survival curves continue in their inexorable drift downward, and an unacceptably small fraction of patients are cured. Attempts to further prolong survival and, perhaps, increase the likelihood of cure include a focus on the anti-CD20 portion of the treatment. Maintenance rituximab prolongs progression-free survival, yet with no impact on overall survival, despite an increase in cost, toxicity, and nuisance.8,9

Enter Next-Generation Anti-CD20 Molecule

Numerous next-generation anti-CD20 molecules have been tested, but abandoned, because they were neither more active than rituximab nor effective in the setting of rituximab resistance. Enter obinutuzumab (Gazyva), a glycoengineered, type II anti-CD20 molecule with less complement-dependent cytotoxicity than rituximab but greater antibody-dependent cellular cytotoxicity (ADCC) and direct cell death. The early randomized phase II GAUSS study comparing single-agent obinutuzumab with rituximab did not generate encouraging results.10 Nonetheless, data from several combination studies stimulated interest in phase III trials.

If we are truly to impact patient outcomes, the primary focus of clinical research should be on front-line therapy.
— Bruce D. Cheson, MD, FACP, FAAAS, FASCO

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The GADOLIN study compared bendamustine/obinutuzumab followed by obinutuzumab maintenance with bendamustine monotherapy in patients considered to be rituximab-refractory and, thus, not expected to benefit from subsequent rituximab.11 Despite similar complete and overall response rates, not only was progression-free survival prolonged, but overall survival was as well, along with improvement in quality of life.12 The explanation for the discrepancy between response rates and time-dependent outcomes was a more-rapid and complete eradication of minimal residual disease with the addition of obinutuzumab,13 suggesting current measures of response assessment require reevaluation in the era of newer therapies.14 These results led to the U.S. Food and Drug Administration (FDA) approval of this regimen in the treatment of patients with relapsed or refractory follicular lymphoma.

Approval in Front-Line Setting

Nonetheless, if we are truly to impact patient outcomes, the primary focus of clinical research should be on front-line therapy. On November 16, 2017, the FDA approved the combination of obinutuzumab with chemotherapy du jour as the initial treatment of follicular lymphoma—the first regimen to have achieved this status. Marcus and coworkers are to be commended for completing the 1,202-patient GALLIUM trial, reviewed in this issue of The ASCO Post, which led to this approval.15

The ever-increasing number of new targeted agents and immunotherapeutics should provide the foundation on which to build active and well-tolerated noncytotoxic strategies.
— Bruce D. Cheson, MD, FACP, FAAAS, FASCO

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In this study, previously untreated patients with follicular lymphoma were treated with bendamustine, CHOP, or CVP with randomization to receive either rituximab or obinutuzumab, followed by antibody maintenance for 2 years. Despite similar complete and overall response rates in the two arms, the study met its primary endpoint of prolongation of progression-free survival as assessed by the investigators. The hazard ratio was 0.66, yet the difference was but 6.7% at 3 years. Unfortunately, the regimen failed to prolong overall survival despite the additional toxicities with obinutuzumab. Quality of life data were not provided. At this time, no clinical or laboratory factors appear to identify patients who might preferentially benefit from the regimen, making the additional toxicities worthwhile.

Yes, patients with follicular lymphoma now have another active, standard regimen for their initial treatment. But, no, we are no closer to our goal of prolonging patient survival with more effective and less toxic therapy.

Emergence of Biologic Doublets

An increasing body of data supports the likelihood of an effective yet chemotherapy-free world for patients with follicular lymphoma. Building on the single-agent activity of rituximab, CALGB investigators beginning in 2004 pioneered the concept of biologic doublets, with impressive results.16,17 The use of lenalidomide (Revlimid) as a rituximab partner led to the so-called R2 regimen, first studied by Leonard et al18 in the relapse setting and subsequently by Fowler et al19 and Martin et al20 as front-line treatment. Results from the latter two studies were extremely impressive, with overall response rates of greater than 90%, complete remissions in about 80% of patients, and impressive progression-free survival curves.

The financial tolerable dose must also factor into the equation, especially with treatments not producing a survival benefit.
— Bruce D. Cheson, MD, FACP, FAAAS, FASCO

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We eagerly await the results of the large completed RELEVANCE trial comparing R2 with rituximab/chemotherapy in untreated follicular lymphoma. If the results favor R2, how will we decide between that regimen and obinutuzumab/chemotherapy? Since obinutuzumab already has enhanced ADCC compared with rituximab, would the addition of lenalidomide further enhance this effect? Should we automatically switch to obinutuzumab/lenalidomide, although it has not yet been reported in the front-line setting?21

Building Noncytotoxic Strategies

The ever-increasing number of new targeted agents and immunotherapeutics should provide the foundation on which to build active and well-tolerated noncytotoxic strategies. They include antibody-based approaches such as the anti-CD19 MOR208, which recently received breakthrough designation in diffuse large B-cell non-Hodgkin lymphoma, and the anti-CD79b antibody-drug conjugate polatuzumab vedotin.22 The FDA approved the phosphoinositide 3-kinase inhibitors idelalisib (Zydelig) in 2016 and copanlisib (Aliqopa) in 2017 for the treatment of patients with relapsed or refractory follicular lymphoma. Others of this class in development, including umbralisib, appear comparably active and perhaps less toxic.


Chemotherapy Regimens


• R-FN


• BR

Combination Therapies

• enalidomide/rituximab

• binutuzumab/

Investigational Doublets

• brutinib/acalabrutinib

• delalisib/copanlisib

• ivolumab/pembrolizumab

Although ibrutinib (Imbruvica),23 the BCL2 inhibitor venetoclax (Venclexta),24 and checkpoint inhibitors exhibit only modest single-agent activity in follicular lymphoma,25 their role as partners in multiagent regimens is worthy of investigation. We are now in a new phase of drug development where multiple same-class agents are receiving regulatory approval for similar indications (eg, ibrutinib and acalabrutinib [Calquence]; idelalisib and copanlisib; nivolumab [Opdivo] and pembrolizumab [Keytruda]). It is our responsibility to try to understand how their differences may impact various patient populations.

Innumerable clinical trials of doublets and triplets of these targeted agents are ongoing. Molecular and genetic correlative studies should identify predictive biomarkers, and novel trial designs should be considered to facilitate study completion. The financial tolerable dose must also factor into the equation, especially with treatments not producing a survival benefit. Taking these elements into consideration will be necessary to pave the way for an effective, personalized chemotherapy-free road leading to the cure of patients with follicular lymphoma in the future. ■

Dr. Cheson is Professor of Medicine; Head of Hematology and Cellular Therapy; Deputy Chief, Division of Hematology-Oncology; Fellowship Program Director, Georgetown University Hospital, Lombardi Comprehensive Cancer Center, Washington, DC.

DISCLOSURE: Dr. Cheson reported no conflicts of interest.


1. Hiddemann W, Kneba M, Dreyling M, et al: Frontline therapy with rituximab added to the combination of cylophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 106:3725-3732, 2005.

2. Marcus R, Imrie K, Solal-Celigny P, et al: A phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol 26:4579-4586, 2008.

3. Herold M, Haas A, Srock S, et al: Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: An East German Study Group Hematology and Oncology Study. J Clin Oncol 25:1986-1992, 2007.

4. 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.

5. 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, multicentre, randomised, phase 3 non-inferiority trial. Lancet 381:1203-1210, 2013.

6. Flinn IW, van der Jagt R, Kahl BS, et al: Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: The BRIGHT study. Blood 123:2944-2952, 2014.

7. Burke JM, van der Jagt RH, Kahl BS, et al: Differences in quality of life between bendamustine-rituximab and R-CHOP/R-CVP in patients with previously untreated advanced indolent non-Hodgkin lymphoma or mantle cell lymphoma. Clin Lymphoma Myeloma Leuk 16:182-190.e1, 2016.

8. 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, randomised controlled trial. Lancet 377:42-51, 2011.

9. Kahl BS, Hong F, Williams ME, et al: Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: Eastern Cooperative Oncology Group protocol E4402. J Clin Oncol 32:3096-3102, 2014.

10. Sehn LH, Goy A, Offner FC, et al: Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: Final analysis of the GAUSS study. J Clin Oncol 33:3467-3474, 2015.

11. Sehn LH, Chua N, Mayer J, et al: Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): A randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol 17:1081-1093, 2016.

12. Cheson BD, Trneny M, Bouabdallah K, et al: Obinutuzumab plus bendamustine followed by obinutuzumab maintenance prolongs overall survival compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma: Updated results of the GADOLIN study. 2016 ASH Annual Meeting. Abstract 615.

13. Pott C, Belada D, Danesi N, et al: Analysis of minimal residual disease in follicular lymphoma patients in GADOLIN, a phase III study of obinutuzumab plus bendamustine versus bendamustine in relapsed/refractory indolent non-Hodgkin lymphoma. 2015 ASH Annual Meeting. Abstract 3978.

14. Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano classification. J Clin Oncol 32:3059-3068, 2014.

15. Marcus R, Davies A, Ando K, et al: Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 377:1331-1344, 2017.

16. Czuczman MS, Leonard JP, Jung S, et al: Phase II trial of galiximab (anti-CD80 monoclonal antibody) plus rituximab (CALGB 50402): Follicular Lymphoma International Prognostic Index (FLIPI) score is predictive of upfront immunotherapy responsiveness. Ann Oncol 23:2356-2362, 2012.

17. Grant BW, Jung SH, Johnson JL, et al: A phase 2 trial of extended induction epratuzumab and rituximab for previously untreated follicular lymphoma: CALGB 50701. Cancer 119:3797-3804, 2013.

18. Leonard JP, Jung SH, Johnson J, et al: Randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma: CALGB 50401 (Alliance). J Clin Oncol 33:3635-3640, 2015.

19. Fowler NH, Davis RE, Rawal S, et al: Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: An open-label phase 2 trial. Lancet Oncol 15:1311-1318, 2014.

20. Martin P, Jung SH, Pitcher B, et al: A phase II trial of lenalidomide plus rituximab in previously untreated follicular non-Hodgkin’s lymphoma (NHL): CALGB 50803 (Alliance). Ann Oncol 28:2806-2812, 2017.

21. Fowler NH, Neelapu SS, Samaniego F, et al: Activity of the immunologic doublet of lenalidomide plus obinutuzumab in relapsed follicular lymphoma: Results of a phase I/II study. 2017 ASCO Annual Meeting. Abstract 7531. Presented June 5, 2017.

22. Pfeifer M, Zheng B, Erdmann T, et al: Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes. Leukemia 29:1578-1586, 2015.

23. Gopal AK, Schuster SJ, Fowler N, et al: Ibrutinib as treatment for chemoimmunotherapy-resistant patients with follicular lymphoma: First results from the open-label, multicenter, phase 2 DAWN study. 2016 ASH Annual Meeting. Abstract 128.

24. Davids MS, Roberts AW, Seymour JF, et al: Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol 35:826-833, 2017.

25. Lesokhin AM, Ansell SM, Armand P, et al: Nivolumab in patients with relapsed or refractory hematologic malignancy: Preliminary results of a phase Ib study. J Clin Oncol 34:2698-2704, 2016.

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