Current Controversies in Lymphoma: From the Role of Liquid Biopsy to Ways to Improve Upon Standard Chemotherapy

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James O. Armitage, MD, FASCO

James O. Armitage, MD, FASCO

Two topics that hematologists are currently grappling with were addressed at the 2019 Debates and Didactics Conference in Sea Island, Georgia, sponsored by Emory University Winship Cancer Institute, by Editor-in-Chief of The ASCO Post, James O. Armitage, MD, FASCO.1 They focus on the emerging role of liquid biopsy and various therapeutic approaches under study to improve outcomes with standard chemotherapy for patients with lymphoma. Dr. Armitage is the Joe Shapiro Professor of Medicine in the Division of Oncology & Hematology at the University of Nebraska Medical Center.


Liquid Biopsy

“Liquid biopsies are the flavor of the month in our business,” Dr. Armitage said. “What are we doing with them, and what should we be doing?”

The term refers to several different assays that measure circulating tumor cells, circulating tumor DNA, and mutations, and there is currently no standard assay. In lymphoma, liquid biopsies are being studied for a variety of uses, including:

  • To make a diagnosis
  • To provide prognostic information (with both quantitative and qualitative assays)
  • To identify targetable mutations not previously found on biopsy (ie, possible spatial variations in their occurrence in the tumor)
  • To monitor for new (hopefully targetable) mutations during treatment, thus predicting disease progression
  • To perform “interim” re-testing to guide therapy
  • To define complete response and minimal residual disease
  • To offer surveillance for relapse (positive tests appear to precede clinical relapse).

Thus far, liquid biopsies have not become standard tests for these purposes. However, it is known that higher levels of circulating cell-free DNA or tumor-specific DNA seem to accompany bulky disease.

“My conclusion is that this is interesting, important research, but it’s not ready for prime time,” Dr. Armitage said. When patients inquire about liquid biopsies—as they have often heard about them—they should probably be told these tests are unlikely to benefit them at this time, he said, although he predicted these tests may eventually change practice.

Improving Upon CHOP-R

The second topic addressed by Dr. Armitage is the optimal treatment of challenging lymphomas. He introduced this topic by describing a 59-year-old man with stage 3 diffuse large B-cell lymphoma (DLBCL) of the ABC (activated B-cell–like) subtype who had an 8-cm mass, was a double-expressor, had a Ki67 index of 70%, and had an elevated lactate dehydrogenase (LDH) level.

“This patient had been on the Internet, as have many of our patients, and he wanted to know if there isn’t something better than CHOP-R [cyclophosphamide, vincristine, doxorubicin, prednisone, rituximab], which is what was recommended to him,” he said.

“This is a very practical question,” Dr. Armitage commented. “It’s been a hot issue for a long time, and there actually are several ways we might do better than CHOP-R.”

The following approaches have been tried, with varying degrees of success:

Different regimens: ACVBP (intensified doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) has been shown to outperform CHOP-R in young, good-risk patients. “However, it’s an extraordinarily aggressive regimen and can be toxic and dangerous if you’re not used to it,” explained Dr. Armitage. It is also difficult to obtain vindesine in the United States.

Increased dose intensity: CHOP-14 was initially shown to be apparently superior to CHOP-21, but this was not confirmed in two more phase III trials.

My conclusion is that liquid biopsy is interesting, important research, but it’s not ready for prime time.
— James O. Armitage, MD, FASCO

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Prephase treatment (pretreatment): Prephase treatment is very low-dose chemotherapy used to reduce the tumor burden, minimize side effects, and prepare newly diagnosed patients for standard-dose chemotherapy. It has been shown to reduce first-cycle treatment-related mortality.

Prolonged infusion: EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) seemed to be more effective than CHOP-R in early studies. However, these findings were not confirmed in a randomized trial.2

Maintenance therapy: Rituximab or lenalidomide has been used as maintenance therapy. However, in a recent study,3 no benefit was shown with rituximab maintenance in patients with a complete response to induction therapy.

Role of Consolidation and Maintenance Therapies

Radiotherapy and autologous stem cell transplant (ASCT) are options for consolidation therapy. Focusing on ASCT, Dr. -Armitage described a 2013 randomized trial in patients with aggressive non-Hodgkin lymphoma.4 The investigators found that ASCT after CHOP or CHOP-R did not improve survival overall but did confer a benefit in a high-risk subset (patients with three negative prognostic factors on the age-adjusted International Prognostic Index).4 At 2 years, progression-free survival was 75% with ASCT vs 41% without transplant (P = .001), and overall survival was 82% vs 64% (P = .01).

Regarding maintenance therapy with rituximab in DLBCL, outcomes seem to be better with maintenance if patients do not receive rituximab at induction. However, if rituximab is given at induction, it does not improve disease-free or overall survival but does add toxicity.


For more on the treatment of lymphomas, see an interview with James O. Armitage, MD, on The ASCO Post Newsreels at

This was recently shown in the HOVON-NORDIC trial, presented at the 2019 International Conference on Malignant Lymphoma in Lugano, Switzerland.3 Disease-free survival at 2 years was about 75% in both the maintenance and observation arms, and overall survival was 84%. However, grade 3 or 4 adverse events were almost tripled with maintenance therapy.

Miscellaneous Regimens

Dr. Armitage said he “regularly” uses a prephase regimen in sicker, elderly patients, although he acknowledged that its benefit has not been proved in a phase III trial. This regimen entails 1 week of high-dose prednisone, sometimes with vincristine.

Dr. Armitage said he still gives EPOCH-R to patients with a Ki67 index higher than 90%, and he considers adjuvant radiotherapy for large primary tumors (mass > 10 cm and primary lesions in the bone). However, again, the benefit of this approach has not been proved. He also considers adjuvant ASCT in high-risk younger patients (based on a subset analysis).

Newest Idea: Adding Other Agents to CHOP-R

The approach that has garnered the most interest lately seems to be the addition of other agents to CHOP-R, the most promising to date being lenalidomide (so-called R2 CHOP). Two studies of this approach were presented this year in Lugano, Switzerland: a randomized phase II ECOG/Intergroup trial in DLBCL, in both the ABC and GCB (germinal center B-cell–like) subtypes5 and the international randomized phase III ROBUST trial in patients with DLBCL who have the ABC subtype.6

The ECOG/Intergroup trial found that overall survival at 2.2 years was 87% with R2 CHOP vs 80% with CHOP-R alone.5 This yielded a hazard ratio of 0.67 (P = .03); however, with a 2-sided P test (as required for a phase III trial), this would miss statistical significance, he noted. The larger ROBUST trial, studying the ABC subtype alone (the subtype in which lenalidomide is supposed work), found no difference between these regimens, with overall survival rates at 2.3 years of 79% and 80%, respectively (hazard ratio = 0.85; P = .29).6

“How do we interpret this information,” asked Dr. Armitage. “We should remember the old adage we were taught in medical school: Don’t be the first or the last to take up a new therapy,” he commented. In other words, the benefit of R2 CHOP-R remains unproved. 

DISCLOSURE: Dr. Armitage has served in a leadership role for Tesaro; owns stock in Tesaro Bio, Inc; and has served in a consulting or advisory role for Ascentage Pharma, Conatus, Lundbeck, Oncology Analytics, Partner Therapeutics, Samus Therapeutics, and Union Pacific.


1. Armitage JO: Perspectives on complex cases in lymphoma. 2019 Debates and Didactics Conference. Lecture. Presented July 25, 2019.

2. Wilson WH, sin-Ho J, Pitcher BN, et al: Phase III randomized study of R-CHOP versus DA-EPOCH-R and molecular analysis of untreated diffuse large B-cell lymphoma: CALGB/Alliance 50303. 2016 American Society of Hematology Annual Meeting & Exposition. Abstract 469.

3. Lugtenburg P, de Nully Brown P, van der Holt B, et al: Rituximab maintenance for patients with diffuse large B-cell lymphoma in first complete remission: Results from a randomized HOVON-NORDIC Lymphoma Group phase III study. Hematol Oncol 37:79-80, 2019.

4. Stiff PJ, Unger JM, Cook JR, et al: Autologous transplantation as consolidation for aggressive non-Hodgkin’s lymphoma. N Engl J Med 369:1681-1690, 2013.

5. Nowakowski GS, Hong F, Scott DW, et al: Addition of lenalidomide to R-CHOP improves outcomes in newly diagnosed diffuse large B cell lymphoma: First report of ECOG-ACRIN 1412. Hematol Oncol 37:37-38, 2019.

6. Vitolo U, Witzig TE, Gascoyne RD, et al: ROBUST: First report of phase III randomized study of lenalidomide/R-CHOP vs placebo/R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma. Hematol Oncol 37:36-37, 2019.