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

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 1 of a 2-part series

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


The management of non-Hodgkin lymphoma (NHL) was transformed with the introduction of rituximab, a chimeric anti-CD20 monoclonal antibody. Today, rituximab is joined by several new and emerging monoclonal antibodies, as well as other targeted therapies, that are demonstrating safety and efficacy in patients with NHL. These novel agents exploit specific tumor pathways, allowing for greater specificity as well as less toxicity. Accordingly, some experts have suggested that the future of NHL may be chemotherapy-free, relying on the use of targeted therapies with greater efficacy and safety. Here, Dr. Anas Younes reviews the most promising emerging agents based on ongoing clinical trials and assesses the potential for predictive biomarkers to aid treatment selection.


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 is the status of the newest and most promising therapies currently on the horizon for indolent non-Hodgkin lymphoma (NHL)?

Dr. Younes: So there are a few new agents that are promising for the treatment of indolent non-Hodgkin lymphoma—and mainly we are talking about indolent B-cell non-Hodgkin lymphoma.1,2 I think the leading compounds are the BTK [Bruton tyrosine kinase] inhibitor ibrutinib and the PI3 [phosphatidylinositol 3] kinase inhibitor idelalisib, which is a PI3 kinase delta-specific inhibitor.

Narrator: Idelalisib has been studied as a single agent in patients with recurrent indolent lymphoma, and its use resulted in significant tumor shrinkage in the majority of patients.3,4 Ibrutinib has shown single-agent activity in follicular lymphoma, including in patients with resistant disease.5 Several trials are evaluating these compounds as monotherapy or in combination with other targeted therapies in patients with indolent NHL.6,7

Dr. Younes: Both are oral drugs that have shown a very good safety profile [in] that they can be administered for a long time with manageable side effects and toxicities; and also they both produce reasonably high response rates that are durable. Both are currently not approved by the FDA, but it is hoped that both of them would be approved at one point for the treatment of patients with indolent B-cell lymphoma.

Other agents fall into two major classes of drugs. One is the antibody-drug conjugates [ADC], and there are a few of them in clinical trials with early signs of potential activity; although, it is too early to call at the present time which one would be a winner. Those ADCs target CD19, CD22, CD79, and there are more on the horizon.

And the other class of agents, which is called the checkpoint blockade inhibitors, mainly the PD-1/PD-L1 monoclonal antibodies. The phase 1 and 2 studies are currently ongoing for B-cell lymphomas, but there are also early encouraging signs that this strategy may be fruitful in the future.

The immunomodulatory agents [IMA] have some activity in follicular lymphoma, and they are currently being incorporated in clinical trials,8,9 although the leading compound, lenalidomide, has not been approved. So for indolent lymphoma, lenalidomide has been combined with rituximab as a doublet to treat patients with newly diagnosed, advanced-stage follicular lymphoma requiring therapy. So this would be the first non-chemotherapy combination regimen—combining lenalidomide with rituximab—that would be compared with standard chemotherapy.

Narrator: As some examples of studies looking at the combination of lenalidomide plus rituximab, a trial from The University of Texas MD Anderson Cancer Center evaluated the combination as an initial treatment for indolent lymphoma.10 The overall response rate was 97%, with the majority of patients achieving complete responses. Further follow-up data from this study are awaited. Another more recent study of lenalidomide plus rituximab included patients with stage III to IV or bulky stage II, grade 1 to 3a, FLIPI  0 to 2 score disease.11 In this trial, the combination showed an overall response rate of 93% and a complete response rate of 70%. There is considerable interest in moving forward with this and other biologic doublets that do not include chemotherapy.

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What is the status of the newest and most promising therapies currently on the horizon for diffuse large B-cell lymphoma (DLBCL)?

Dr. Younes: One can consider the same agents [outlined above, as they are] also showing some activity in diffuse large B-cell lymphomas. Ibrutinib preferentially has activity in the non-GCB—[or] non–germinal center type—mainly the ABC subtype or the activated B-cell lymphoma subtype of diffuse large B-cell lymphoma.12

The PI3 kinase inhibitors as a class have not shown much activity in diffuse large B-cell lymphoma.3 Somehow, if you treat with mTOR inhibitors, which is [targeting] downstream of the PI3 kinase, there seem to be higher response rates compared with PI3 kinase inhibitors. So, for example, with everolimus or temsirolimus, one can achieve a 30% response rate range,13-16 compared with a less than 10% response rate for the PI3 kinase inhibitors. But this is a pathway of interest that is frequently activated in diffuse large B-cell lymphoma, and I think we'll see more trials targeting this pathway in the future.

In diffuse large B-cell lymphoma, there are data to suggest that lenalidomide has preferential activity also in the ABC subtype.17-20 And based on these data, there are two trials combining lenalidomide with R-CHOP concurrently or giving lenalidomide in maintenance or adjuvant setting after R-CHOP chemotherapy. Those trials are ongoing, and hopefully we'll get some information, again, in the next few years from now.

Narrator: Currently available data from the trials integrating lenalidomide in the R-CHOP regimen have shown an acceptable toxicity profile. The two-year overall survival was greater than 90%, and the two-year progression-free survival rate was 75% to 80%.19 A retrospective analysis also indicated that most of the benefit from adding lenalidomide to R-CHOP was limited to the patients with a non-GCB phenotype.20

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Where do we stand with the identification and clinical use of predictive biomarkers to determine which patients with NHL would benefit from which agent and/or combination—especially related to the use of emerging therapies?

Dr. Younes: I think the biggest question is, if you have drugs that can work potentially across two different histologies, like follicular lymphoma and diffuse large B-cell lymphoma, can we also treat beyond these two histologies using the same agent? And, if so, do we have a biomarker to select patients who are likely to benefit from these treatment strategies across different histologies?

The short answer? No. For large [B]-cell lymphoma, we primarily depend on dichotomizing it to a GCB/ABC or non–GCB and GCB subtypes. But we, and others also, are looking at more specific biomarkers that can select patients to specific therapies.

At the present time, many investigators and centers, including ours here at Memorial Sloan-Kettering, are performing genetic mutation analysis on patients receiving therapy with investigational agents, or even with standard agents, to see if we can correlate certain mutations with response or resistance to specific therapy. There are also immunohistochemistry biomarkers, such as MYC and BCL2, that can potentially help in the future, guiding therapy.21-25

Narrator: In studies of patients with DLBCL, the coexpression of MYC and BCL2 predicted a lower complete response rate and shorter progression-free and overall survival.22,23 Furthermore, in a recent analysis of more than 800 patients with de novo DLBCL treated with R-CHOP, the coexpression of MYC and BCL2 was associated with inferior overall and progression-free survival.25 Further studies are needed to clarify the prognosis of lymphomas that overexpress BCL2 and MYC based on immunohistochemistry.

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  2. Seiler TM, Hiddemann W. Curr Opin Oncol. 2012;24:742-747.
  3. Kahl BS et al. 52nd ASH Annual Meeting and Exposition (ASH 2010). Abstract 1777.
  4. Furman RR et al. ASH 2010. Abstract 55.
  5. Fowler N et al. ASH 2010. Abstract 964.
  6. Accessed December 9, 2013.
  7. Accessed December 9, 2013.
  8. Kimby E. Curr Hematol Malig Rep. 2012;7:221-227.
  9. Desai M et al. J Hematol Oncol. 2013;6:55.
  10. Fowler NH et al. J Clin Oncol. 2010;28(15s): Abstract 8036.
  11. Martin P et al. Hematol Oncol. 2013;31(suppl 1):117.
  12. Safety and Efficacy Study of Bruton's Tyrosine Kinase Inhibitor in Subjects With Relapsed or Refractory Diffuse Large B-cell Lymphoma. Accessed December 9, 2013.
  13. Smith SM et al. J Clin Oncol. 2010;28:4740-4746.
  14. Ansell SM et al. Cancer. 2008;113:508-514.
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  16. Witzig TE et al. Leukemia. 2011;25:341-347.
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  18. Hernandez-Ilizaliturri FJ et al. Cancer. 2011;117:5058-5066.
  19. Chiappella A et al. 54th ASH Annual Meeting and Exposition (ASH 2012). Abstract 903.
  20. Nowakowski GS et al. ASH 2012. Abstract 689.
  21. Akyurek N et al. Cancer. 2012;118:4173-4183.
  22. Johnson NA et al. J Clin Oncol. 2012;30:3452-3459.
  23. Green TM et al. J Clin Oncol. 2012;30:3460-3467.
  24. Horn H et al. Blood. 2013;121:2253-2263
  25. Hu S et al. Blood. 2013;121:4021-4031.

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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

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