NHL Cases in Point: Applying Current Evidence to Challenging Patient Scenarios

Course Director

Anas Younes, MD

Anas Younes, MD
Chief, Lymphoma Section
Division of Hematologic Oncology
Department of Medicine
Memorial Sloan-Kettering
Cancer Center
New York, New York

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Part 2 of a 2-part series

Dr. Younes provides expert feedback to the questions submitted by your peers during a recent survey on this topic.


Today, the chimeric anti-CD20 monoclonal antibody rituximab combined with chemotherapy remains a standard of care for patients with non-Hodgkin lymphoma (NHL). However, ongoing studies of new and emerging targeted therapies, including monoclonal antibodies, antibody-drug conjugates, immunomodulatory agents, and others, suggest that the future of NHL may move towards more tailored and less aggressive approaches, based on use of these novel agents with greater efficacy and safety profiles. While clinicians wait for the outcomes of these studies, they continue to face difficult treatment decisions. In this activity, Dr. Anas Younes outlines practical guidance for some challenging patient care scenarios.


This activity is supported by an educational grant from Celgene Corporation.
Additional support provided by Penn State College of Medicine and Answers in CME.

Course Director
Anas Younes, MD, has a financial interest/relationship or affiliation in the form of:
Grant/Research Support from Genentech, Inc.; Gilead; Infinity Pharmaceuticals, Inc.; Johnson & Johnson Services, Inc.; Merck & Co., Inc.; Novartis Corporation; and Seattle Genetics, Inc.
Honoraria from Celgene Corporation; Curis Inc.; Incyte Corporation; Millennium Pharmaceuticals, Inc.; Novartis Corporation; Pharmacyclics, Inc.; sanofi-aventis; and Seattle Genetics, Inc.
Medical Director
Kadrin Wilfong, MD
Answers in CME, Inc.
Kadrin Wilfong, MD, currently has no financial interests/relationships or affiliations in relation to this activity.

Answers in CME staff who may potentially review content for this activity have disclosed no relevant financial relationships.

Penn State College of Medicine staff and faculty involved in the development and review of this activity have disclosed no relevant financial relationships.

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What options would you consider for a patient initially diagnosed with asymptomatic follicular lymphoma who, after several years of watch-and-wait, develops B symptoms?

Dr. Younes: So although the watch-and-wait policy has been implemented for many years for patients with advanced-stage follicular lymphoma who are asymptomatic, I think this strategy is fading away based on the LymphoCare analysis, which showed the vast majority of patients are treated.1 In lieu of watch and wait, I think many oncologists now are electing to treat patients with either rituximab alone or even with combination of rituximab and other agents.1

However, if one, let's say, has a patient who [was] observed for, let's say, two to three years with no therapy and the patient was not symptomatic, and now the patient is developing symptoms or signs requiring therapy, there are now two widely used approaches for such a patient. One is the use of bendamustine plus rituximab [R]2,3 and the other one is to use standard R-CHOP [cyclophosphamide-doxorubicin-vincristine-prednisone] chemotherapy.4-6 There is an advantage and a disadvantage for using either one alone. There are data now to suggest that bendamustine plus rituximab can produce longer progression-free survival [PFS], which means longer disease control. But there's not much data about the impact on survival yet.

Narrator: Bendamustine plus rituximab was compared with standard R-CHOP for six cycles in a randomized, phase 3 trial of patients with advanced indolent or mantle-cell lymphomas.2 The bendamustine arm showed superior median progression-free survival (69.5 versus 31.2 months) for all histologic subtypes except marginal zone lymphoma. Less toxicity was observed as well, including lower rates of grade 3 and 4 neutropenia and leukocytopenia, fewer infectious episodes, less paresthesia and stomatitis, and no alopecia. There was no difference in overall survival (OS) at a median follow-up of 45 months. The long-term toxicity profile and impact on future treatments are unknown at this time.

Standard R-CHOP was compared with R-CVP (cyclophosphamide-vincristine-prednisone) and R-FM (fludarabine-mitoxantrone) in a randomized trial of 534 patients with advanced-stage follicular lymphoma.5 The R-CHOP and R-FM arms were associated with superior rates of three-year PFS and time to treatment failure, versus R-CVP; a survival analysis was not performed. R-FM had higher rates of severe neutropenia and second malignancies.

Dr. Younes: For the average patient who becomes symptomatic and, let's say, has a borderline heart function or has some signs of potential histologic transformation—and this is usually indicated by areas in the PET scan that show a high SUV value—one would probably attempt to then select either/or [approach]. So with a borderline left ventricular ejection fraction, I would stay away from anthracycline-based regimen, and I would use a bendamustine-based regimen. If there's an early indication of histologic transformation, then my preference is to use R-CHOP chemotherapy instead of R-bendamustine.

Narrator: Support for this approach is provided by retrospective analyses of patients with histologic transformation and extrapolation of data from patients with de novo diffuse large B-cell lymphoma (DLBCL). Retrospective studies suggest that some patients who have received little prior therapy treated with chemoimmunotherapy alone have five-year survival rates of approximately 60%.7-9

Dr. Younes: Outside these two scenarios, I think it's patient-physician preference and one can use either one of these regimens, knowing that if one starts with R-bendamustine and the patient has relapsed disease or progression after a few years, you can treat with R-CHOP and vice versa.

For patients who achieve a remission after R-CHOP or R-bendamustine, would you do a maintenance rituximab? There are data for the R-CHOP regimen.10 There are not much data about R-bendamustine, but one thinks that the principle should hold for either one; although, this needs to be tested in a clinical trial. But it is also an option to then follow up with maintenance rituximab, especially for those who have positive PET residual lesions at the end of R-CHOP chemotherapy. There may be some benefit for prolonging the time to next therapy and the time to progression.

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For a 59-year-old male patient with newly diagnosed, poor-prognosis diffuse large B-cell lymphoma, would you offer standard therapy or clinical trial enrollment with investigational therapies? If the latter, what options would you consider?

Dr. Younes: Outside of clinical trials, R-CHOP remains the most widely used regimen for these patients.

Narrator: Use of this therapy is supported by studies that have shown that rituximab-containing CHOP or CHOP-like regimens provide superior survival to the same regimen without rituximab, regardless of the patient's age, with almost no increase in toxicity.11-20

Dr. Younes: However, there are several clinical trials that are trying to improve on the outcome of patients with R-CHOP, especially for those who have the ABC subtype or non-GCB subtype [of DLBCL] because these patients don't do as well with R-CHOP chemotherapy compared with those who have the GCB subtype.

So there are several trials now that are trying to capture these patients. One of them is randomizing patients with diffuse large B-cell lymphoma with non-GCB subtype to receive either standard R-CHOP chemotherapy or R-CHOP plus ibrutinib,21 which is the oral BTK inhibitor. This is an ongoing international trial that is selecting patients with non-GCB subtype using immunohistochemistry criteria.

There are other trials that are also combining R-CHOP, either concurrently or in sequence, with lenalidomide,22,23 also preferentially trying to capture patients with the ABC subtype because these are the ones who have more unmet medical need compared to GCB and also because these patients [with the ABC subtype] seem to benefit more with lenalidomide compared with the GCB subtype.

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What options, if any, would you consider for maintenance therapy after first-line chemoimmunotherapy in a patient with diffuse large B-cell lymphoma?

Dr. Younes: Would any of these patients benefit from maintenance strategy outside a clinical trial? The answer is no. There are no data to show there is any added value for maintenance strategy after R-CHOP chemotherapy in patients who are responding.15,24 However, this question is currently being answered in several clinical trials, and we'll find out if this strategy will be beneficial in the future.

Examples of clinical trials looking at introducing a novel agent in the maintenance manner after induction with R-CHOP chemotherapy is lenalidomide, for example.25 It's given in adjuvant setting. There is another trial that introduced the mTOR inhibitor everolimus also in adjuvant setting.26 And there are trials that looked also at radioimmunotherapy as consolidation. This will not qualify as purely maintenance, but it's an adjuvant or consolidation therapy.

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  1. Friedberg JW et al. J Clin Oncol. 2012;30:3368-3375.
  2. Rummel MJ et al. Lancet. 2013;381:1203-1210.
  3. Flinn I et al. 54th ASH Annual Meeting and Exposition (ASH 2012). Abstract 902.
  4. Hiddemann W et al. Blood. 2005;106:3725-3732.
  5. Federico M et al. J Clin Oncol. 2013;31:1506-1513.
  6. Czuczman MS et al. J Clin Oncol. 2004;22:4711-4716.
  7. Savage KJ et al. Blood. 2007;110:243a (Abstract 790).
  8. Villa D et al. J Clin Oncol. 2013;31:1164-1171.
  9. Ban-Hoefen M et al. Br J Haematol. 2013;163:487-495.
  10. Cheah CY et al. Future Oncol. 2013;9:1283-1298.
  11. Sehn LH et al. J Clin Oncol. 2005;23:5027-5033.
  12. Pettengell R et al. Br J Haematol. 2003;121:44-48.
  13. Coiffier B et al. N Engl J Med. 2002;346:235-242.
  14. Feugier P et al. J Clin Oncol. 2005;23:4117-4126.
  15. Habermann TM et al. J Clin Oncol. 2006;24:3121-3127.
  16. Pfreundschuh M et al. Lancet Oncol. 2008;9:105-116.
  17. Coiffier B et al. J Clin Oncol. 2007;25(18s): Abstract 8009.
  18. Coiffier B et al. Blood. 2010;116:2040-2045.
  19. Pfreundschuh M et al. Lancet Oncol. 2006;7:379-391.
  20. Pfreundschuh M et al. Lancet Oncol. 2011;12:1013-1022.
  21. Clinicaltrials.gov: A Study of the Bruton's Tyrosine Kinase Inhibitor, PCI-32765 (Ibrutinib), in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma. http://clinicaltrials.gov/ct2/show/NCT01855750. Accessed December 19, 2013.
  22. Clinicaltrials.gov: Rituximab and Combination Chemotherapy With or Without Lenalidomide in Treating Patients With Newly Diagnosed Stage II-IV Diffuse Large B Cell Lymphoma. http://clinicaltrials.gov/ct2/show/NCT01856192. Accessed December 19, 2013.
  23. Clinicaltrials.gov: Lenalidomide With or Without Rituximab After Standard Chemotherapy in Treating Patients With Diffuse Large B-Cell Non-Hodgkin Lymphoma. http://clinicaltrials.gov/ct2/show/NCT00765245. Accessed December 19, 2013.
  24. Morrison VA et al. J Clin Oncol. 2007;25(18s): Abstract 8011.
  25. Clinicaltrials.gov: Study of Lenalidomide Maintenance Versus Placebo in Responding Elderly Patients With DLBCL and Treated With R-CHOP (REMARC). http://clinicaltrials.gov/ct2/show/NCT01122472. Accessed December 19, 2013.
  26. Clinicaltrials.gov: Phase III Study of RAD001 Adjuvant Therapy in Poor Risk Patients With Diffuse Large B-Cell Lymphoma (DLBCL) of RAD001 Versus Matching Placebo After Patients Achieved Complete Response With First-Line Rituximab-chemotherapy (PILLAR2). http://clinicaltrials.gov/ct2/show/NCT00790036. Accessed December 19, 2013.

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Celgene Corporation

This activity is supported by an educational grant from Celgene Corporation.
Additional support provided by Penn State College of Medicine and Answers in CME.

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Q&A: Current Challenges and New Opportunities in the Management of Non-Hodgkin Lymphoma

  1. An Update on Clinical Trials Evaluating Chemotherapy-Free Approaches to NHL