Current state of lymphoma care

Classical Hodgkin lymphoma

Lymphomas are a diverse group of blood cancers with varied causes, symptoms, treatments and prognoses.¹ These malignancies, which are among the top 10 most common cancers worldwide, show increasing prevalence.¹ Typically, lymphomas are categorised into two main types: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), making up about 10% and 90% of cases, respectively (Figure 1).^1-3

Figure 1. Global burden of lymphoma^2,3

HL is an uncommon monoclonal lymphoid neoplasm typically affecting young adults and originating in cervical lymph nodes.⁴ It is marked by scattered large mononuclear Hodgkin cells and multinucleated Reed–Sternberg cells (abnormal B lymphocytes) amid a background of non-neoplastic inflammatory cells.

Overall, HL has an excellent prognosis, although outcomes depend on various factors⁴

The disease is categorised into two distinct types: classical Hodgkin lymphoma (cHL) and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL).⁴

Approximately 95% of all HL cases are cHL, which can be further divided into four subgroups: nodular sclerosis (NSHL), lymphocyte-rich (LRHL), mixed cellularity (MCHL) and lymphocyte-depleted (LDHL).⁴

Treatment strategies for cHL involve a combination of modalities. The usual standard of care includes combined modality therapy, which combines chemotherapy with antibody–drug conjugates and radiotherapy.^5,6 As a first-line option, patients typically receive a combination of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) and, more recently, brentuximab vedotin, an anti-CD30 antibody–drug conjugate.^5,6 For second-line treatment, options may involve chemotherapy and autologous stem cell transplantation (ASCT), with consolidation therapy incorporating brentuximab vedotin recommended for patients at high risk.^7,8 Additionally, brentuximab vedotin is used in salvage therapy, often in combination with anti-PD-1 immunotherapies, such as pembrolizumab and nivolumab.^7,9 Ongoing investigations explore the use of anti-PD-1 immunotherapies in earlier settings, including their combination with brentuximab vedotin and their impact on patients at high risk of ASCT failure.^5,10 While this approach is relatively new, long-term evidence regarding its outcomes is still emerging, with real-world data becoming available more recently.^5,11,12

Peripheral T-cell lymphomas

Peripheral T-cell lymphoma (PTCL) is a rare, heterogeneous neoplasm that arises from mature T-cell lymphocytes and natural killer cells.¹³ It falls within the category of non-Hodgkin lymphoma (NHL). PTCL represents a minority (10–15%) of all NHLs but comprises a diverse group of diseases, with over 30 different subtypes.¹³ The World Health Organization (WHO) broadly classifies PTCLs as leukaemic, cutaneous/extranodal, or nodal types to reflect their primary manifestation and progression patterns.¹⁴ Among the subtypes, the most common are nodal PTCLs, including PTCL not otherwise specified (NOS), anaplastic large-cell lymphoma (ALCL), and nodal T-follicular helper cell lymphoma (TFHL), which encompasses angioimmunoblastic T-cell lymphoma.

The primary treatment for the common PTCL subtypes remains anthracycline-based chemotherapy, specifically cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP).¹³ Additionally, cyclophosphamide, doxorubicin and prednisone in combination with brentuximab vedotin (CHP-BV) has been approved by the US Food and Drug Administration (FDA) for frontline treatment of CD30+ PTCLs after clinical success of this combination in the ECHELON-2 clinical trial.^13,15,16

The ECHELON-2 clinical trial compared CHOP and CHP-BV in patients with newly diagnosed CD30+ PTCLs and ALCL.¹⁶ After 3 years, median progression-free survival (PFS) was 48.2 months in the CHP-BV group and 20.8 months in the CHOP group (HR 0·71; 95% CI, 0·54–0·93; P=0·0110). This amounted to a 29% decrease in the risk of a PFS event. Overall survival, complete response and overall response were also significantly improved in the CHP-BV groups compared with the CHOP groups.¹⁶ At 5 years of follow up, PFS rates were 51.4% and 43% (P<0.01) for CHP-BV and CHOP, respectively, and overall survival rates were 70% and 61% (P=0.04).¹⁷ These results highlight that CHP-BV is an effective frontline treatment for CD30+ PTCLs and ALCL.

R/R diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most commonly occurring lymphoma and accounts for 25–30% of all non-Hodgkin lymphomas (NHL).¹⁸ DLBCL is more common among White people, followed by African Americans and people of Asian descent. It predominantly affects males and typically presents around the age of 64 years. The overall incidence rises significantly with advancing age.¹⁸

The majority of people diagnosed with DLBCL are successfully treated with initial chemoimmunotherapy. However, 30–40% will experience disease relapse.¹⁹ Salvage chemotherapy followed by autologous stem cell transplant (ASCT) has been the standard approach for these cases,¹⁹ yet recent research has revealed that patients with primary refractory or early relapsed DLBCL do not derive significant benefit from ASCT. Consequently, alternative treatment options are now under investigation.¹⁹

Significant advances have occurred in the management of relapsed/refractory (R/R) DLBCL due to the emergence of chimeric antigen receptor (CAR) T-cell therapy.²⁰ Notably, the TRANSFORM and ZUMA-7 trials have demonstrated favourable outcomes with manageable toxicity profiles.^21,22 As a result, regulatory approval has been granted for lisocabtagene maraleucel (liso-cel)²³ and axicabtagene ciloleucel (axi-cel)²⁴ as second-line therapies for R/R DLBCL.

The US Food and Drug Administration (FDA) has approved two antibody–drug conjugates, polatuzumab vedotin²⁵ and loncastuximab tesirine,²⁶ for the treatment of R/R DLBCL. Additionally, the efficacy of brentuximab vedotin combined with lenalidomide and rituximab, compared with placebo plus lenalidomide and rituximab, is being evaluated in the phase 3 ECHELON-3 clinical trial.²⁷

ADCs/bispecifics in lymphoma

More recently, the introduction of bispecific antibodies (BsAbs) and antibody–drug conjugates (ADCs) has provided additional treatment options for improving lymphoma outcome. ADCs deliver chemotherapy directly to cancer cells, while BsAbs activate the immune system to target tumours.^28,29

The US Food and Drug Administration (FDA) has approved three ADCs for the treatment of classical Hodgkin lymphoma (cHL), systemic anaplastic large-cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL), and certain forms of B-cell lymphoma.^25,26,30 Approved treatments include brentuximab vedotin,³⁰ polatuzumab vedotin²⁵ and loncastuximab tesirine.²⁶

BsAbs that have received regulatory approval or are under investigation are listed below.^28,29

Mosunetuzumab

Mosunetuzumab has received conditional approval from the European Medicines Agency (EMA) and accelerated FDA approval for patients with relapsed or refractory follicular lymphoma (R/R FL) who have had two or more lines of systemic therapy.^31,32

CELESTIMO: This randomised, multicentre, open-label phase 3 study is evaluating the efficacy and safety of mosunetuzumab, compared with rituximab plus lenalidomide, in patients with R/R FL who have had one or more lines of systemic therapy.³³

SUNMO: This phase 3 trial is evaluating the efficacy and safety of mosunetuzumab in combination with polatuzumab vedotin versus rituximab in combination with gemcitabine plus oxaliplatin in patients with R/R aggressive B-cell non-Hodgkin lymphoma.³⁴

Glofitamab

Glofitamab has been approved by the FDA for treatment of DLBCL and LBCL arising from FL and by the EMA for DLBCL.^35,36

GO41944: This global, randomised, open-label phase 3 trial is assessing the safety and efficacy of glofitamab plus gemcitabine and oxaliplatin (GemOx), compared with rituximab plus GemOx, in patients with R/R DLBCL.³⁷

Epcoritamab

Epcoritamab has been approved by both the FDA and EMA for treatment of DLBCL.^38,39

EPCORE FL-1 and EPCORE DLBCL-1: These trials are evaluating the efficacy and safety of epcoritamab in combination with rituximab and lenalidomide in patients with FL and epcoritamab as monotherapy compared with investigator’s choice in DLBCL.^40,41

Odronextamab

OLYMPIA-5: This study is investigating the safety and efficacy of odronextamab combined with lenalidomide, compared with rituximab combined with lenalidomide, in participants with R/R FL and marginal zone lymphoma.⁴²