Despite the increasing number of novel agents and the development of chemotherapy-free regimens, chemotherapy remains a cornerstone of treatment for lymphomas – both in the frontline and salvage settings.

Chemotherapy as frontline standard of care


In diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin lymphoma (NHL), 50-60% of patients are cured with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemoimmunotherapy in the first line.1 Meanwhile, patients with early-stage Hodgkin lymphoma (HL) are typically treated with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy followed by radiation.2

One of the most critical developments in the treatment of these diseases over the last few years is the addition of novel agents to existing chemotherapy backbones. Just last year for example, the ECHELON-1 (NCT01712490) Phase III study found combining antibody-drug conjugate (ADC) brentuximab vedotin with AVD (doxorubicin, vinblastine, dacarbazine) chemotherapy prolonged overall survival (OS), progression-free survival (PFS), and reduced the need for subsequent therapy in patients with advanced-stage HL.3 This led to the regimen becoming a preferred frontline option for these patients.2  

In this video, Swetha Kambhampati, MD, City of Hope, Duarte, CA, highlights how novel agents are being combined with chemotherapy in both the frontline and salvage treatment of HL. She discusses the ECHELON-1 study, and expresses her excitement over an ongoing Phase III trial (NCT03907488) comparing the outcomes of patients with newly diagnosed stage III or IV classic HL treated with either nivolumab or brentuximab vedotin in combination with chemotherapy. 


In DLBCL, the Phase III POLARIX (NCT03274492) trial in intermediate- or high-risk patients, showed pola-R-CHP (polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone) significantly improved PFS compared with R-CHOP,4 and thus the regimen is anticipated to receive regulatory approval as a new standard of care.5 

Risk-adapted treatment


Hodgkin lymphoma 

In addition to the implementation of novel agents, risk- and response-adapted treatment strategies are emerging in the lymphoma field. In HL, for instance, choice of treatment is dependent on factors such as disease histology and stage,2 the presence of poor prognostic features and bulky disease (a single site of disease >10 cm in diameter),2 as well as patient age, sex and comorbidities.6 Moreover, positron emission tomography (PET) scanning is being implemented in the course of treatment for HL to guide treatment de-escalation and intensification decisions.2,7 


In this video, Ninja Övergaard, PhD, Uppsala University, Uppsala, Sweden, describes a retrospective population and registry-based study that compared outcomes of older classical HL patients treated with different first-line chemotherapy regimens in Sweden, Denmark and Norway.8 

She explains how, in patients aged 60 years and over, outcomes are less favorable, due to patient frailty, the increased prevalence of comorbidities, and their greater susceptibility to toxicity from treatment. Moreover, an optimal chemotherapy backbone has not been identified. “All of these factors can hamper the delivery of effective treatment, which can result in treatment failure or relapse,” says Dr Övergaard. 

The study included 1,554 patients with a median age of 70 years, 671 received ABVD, 122 AVD, 465 CHOP and 296 other single-agent or combination chemotherapy.8 “When we looked at the five-year OS, there was no significant difference between the ABVD and AVD groups, irrespective of stage, but patients who received CHOP or other chemotherapy had a significantly lower OS,” explains Dr Övergaard. 

Due to its lesser toxicity with the omission of bleomycin, and equivalent performance in terms of OS, the investigators concluded that AVD is a preferable treatment, and should be the backbone used in prospective studies with novel drugs.8 

Diffuse large B-cell lymphoma 

In DLBCL, a key aspect of treatment selection is whether patients are double or triple hit,9 as high-grade B-cell lymphomas with MYC and BCL2 or BCL6 rearrangements have been shown to have poor outcomes with upfront R-CHOP.10-12 Although no optimal treatment has been established for these patients,13 dose-adjusted (DA) EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab)14 and high intensity regimens such as R-Hyper-CVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) are recommended by the NCCN 2023 guidelines over R-CHOP.13

Here, Gerardo Musuraca, MD, of the IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST), Meldola, Italy, discusses the current approach to managing DLBCL, highlighting the importance of identifying double and triple hit molecular subtypes. 

PET-guided risk-adaptation strategies are also under investigation in DLBCL.5 A recent study found PET scanning after two cycles of chemotherapy (PET2) could predict which patients were at high risk of progression and death in two large independent prospective cohorts.15 The authors advise that, since they could benefit patients, such PET-guided risk-adapted therapy strategies should be the focus of clinical trials.15 


Chemotherapy beyond the first line



Aside from its role in the care of previously untreated patients, chemotherapy also acts as salvage, particularly followed by transplant, in the lymphoma field. For relapsed/refractory (R/R) HL, high-dose chemotherapy (HDCT)  followed by an autologous stem cell transplant (ASCT) is the standard of care.2 Transplanteligible patients with R/R DLBCL are treated with the same approach,1,5 though many will not be salvaged successfully both as a result of unfavorable molecular features and resistance to therapy.1

In this video, Sanjal Desai, MD, University of Minnesota Medical School, Minneapolis, MN, elaborates on the application of salvage chemotherapies in patients with R/R HL and NHL. She describes how recently, regimens incorporating checkpoint inhibitors, brentuximab vedotin and minimal chemotherapy have gained prevalence in R/R HL, while in NHL such novel combinations have failed to show encouraging results, leaving options limited 


Here, Krish Patel, MD, of the Swedish Cancer Institute, Seattle, WA, comments on the results of a Phase II trial (NCT03736616) assessing a novel salvage regimen of acalabrutinib plus R-ICE (rituximab, ifosfamide, carboplatin, etoposide) chemotherapy in transplanteligible patients with R/R DLBCL.16 The study met its endpoint of improving the complete response (CR) rate in these patients and, as Dr Patel explains, after three cycles of therapy, 50% of patients in the current cohort achieved CR, compared with 30% in the historical control. Additionally, almost 70% of patients were able to be taken to potentially curative ASCT. 

Chemotherapy is also among the regimens used for salvage in the up to 60% of large B-cell lymphoma (LBCL) patients who progress following CAR-T therapy.17 However, as discussed by Gloria Iacoboni, MD, Vall d’Hebron University Hospital, Barcelona, Spain, in this video, a retrospective multicenter study comparing chemotherapy, rituximab-polatuzumab-bendamustine (POLA), bispecific antibodies (BiTEs) and immune checkpoint inhibitors in this setting found that polatuzumab-containing regimens and bispecific antibodies yielded higher response rates and improved progression-free survival (PFS).17

Overall, the applications of chemotherapy across different lymphomas are wide reaching, and increasingly being optimized with the addition of novel agents and adoption of risk- and response-adapted strategies. Even after 20 years as standard of care, chemotherapies remain fundamental in the treatment paradigm for both NHL and HL. 


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  2. Ansell SM. Hodgkin lymphoma: 2023 update on diagnosis, risk‐stratification, and Management. American Journal of Hematology. 2022 Sep 19;97(11):1478–88. 
  3. Ansell SM, Radford J, Connors JM, et al. Overall survival with brentuximab vedotin in stage III or IV Hodgkin’s lymphoma. New England Journal of Medicine. 2022 Jul 28;387(4):310–20.  
  4. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. New England Journal of Medicine. 2022 Jan 27;386(4):351–63.  
  5. Ngu H, Takiar R, Phillips T, et al. Revising the treatment pathways in lymphoma: New standards of care—how do we choose? American Society of Clinical Oncology Educational Book. 2022 May 20;(42):629–42.  
  6. Hoppe RT, Herrera AF, Rosenspire KC, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Version 2.2023 Hodgkin Lymphoma (Age ≥18 years). National Comprehensive Cancer Network, Inc.; 2022. Available at: 
  7. Mauz-Körholz C, Landman-Parker J, Fernández-Teijeiro A, et al. Response-adapted omission of radiotherapy in children and adolescents with early-stage classical Hodgkin lymphoma and an adequate response to vincristine, etoposide, prednisone, and doxorubicin (Euronet-PHL-C1): A titration study. The Lancet Oncology. 2023 Mar;24(3):252–61.  
  8. Övergaard N, Lia K, Asdahl P, et al. T082: Avd – a possible golden standard in the first-line treatment of older classical hodgkin lymphoma patients. HemaSphere. 2022 Oct;6:37–8.  
  9. Vodicka P, Klener P, Trneny M. Diffuse large B-cell lymphoma (DLBCL): Early patient management and emerging treatment options. OncoTargets and Therapy. 2022 Dec 6;Volume 15:1481–501.  
  10. Savage KJ, Johnson NA, Ben-Neriah S, et al. MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood. 2009 Oct 22;114(17):3533–7.  
  11. Barrans S, Crouch S, Smith A, et al. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of Rituximab. Journal of Clinical Oncology. 2010 May 10;28(20):3360–5. 
  12. Rosenwald A, Bens S, Advani R, et al. Prognostic significance of myc rearrangement and translocation partner in diffuse large B-cell lymphoma: A study by the Lunenburg Lymphoma Biomarker Consortium. Journal of Clinical Oncology. 2019 Sep 9;37(35):3359–68.  
  13. Zelenetz AD, Fayad LE, Narkhede M, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Version 2.2023 B-Cell Lymphomas. National Comprehensive Cancer Network, Inc.; 2023. Available at: 
  14. Dunleavy K, Fanale MA, Abramson JS, et al. Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in untreated aggressive diffuse large B-cell lymphoma with MYC rearrangement: A prospective, multicentre, single-arm phase 2 study. The Lancet Haematology. 2018 Dec;5(12).  
  15. Desai SH, Pederson L, LaPlant B, et al. PET2 response associated with survival in newly diagnosed diffuse large B-cell lymphoma: Results of two independent prospective cohorts. Blood Cancer Journal. 2022 May 3;12(5).  
  16. Bailey N, Braun T, Bailey M, et al. Initial efficacy and safety of acalabrutinib plus rice in transplant eligible patients with relapsed/refractory diffuse large B-cell lymphoma. Blood. 2022 Nov 15;140(Supplement 1):3765–6. 
  17. Iacoboni G, Iraola-Truchuelo J, Mussetti A, et al. Salvage treatment with novel agents is preferable to standard chemotherapy in patients with large B-cell lymphoma progressing after chimeric antigen receptor T-cell therapy. Blood. 2022 Nov 15;140(Supplement 1):378–80.  
Written by Hannah Balfour
Edited by Elitsa Kamberska & Thomas Southgate

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