Primary mediastinal B-cell lymphoma or PMBCL, a rare type of non-Hodgkin lymphoma (NHL) sometimes called primary thymic mediastinal lymphoma, is an aggressive diffuse large B cell lymphoma (DLBCL) originating in the mediastinum, and mainly expresses B cell surface molecules, such as CD19, CD20, CD22, andCD79a.

PMBCL has a good prognosis if remission is rapidly achieved with dose‐intensive immunochemotherapy. However, because PMBCL is relatively uncommon, clinical management varies across treatment centers, without a single standard of care.[1]

Although there are a variety of upfront chemotherapeutic approaches, to-date, there is no consensus on the optimal regimen. In addition, the use of mediastinal radiotherapy, primarily designed to consolidate treatment responses, also varies across treatment centers. In most cases, the focus is on reducing the exposure to radiotherapy because, in this patient population of young and predominantly female population, radiotherapy may increases the risk of second malignancies and coronary or valvular heart disease.[1][2]

Omitting Radiotherapy
Ongoing research shows that radiation therapy for patients diagnosed with primary mediastinal B-cell lymphoma can be omitted in patients who have a complete metabolic response after chemoimmunotherapy.

This conclusion is based on results from the IELSG37 international study, the largest prospective study of primary mediastinal B-cell lymphoma. The outcomes of the study demonstrated that these patients may be spared from late toxicities without compromising the chances of cure.

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The results of the study, funded, in part, by International Extranodal Lymphoma Study Group (IELSG), the Swiss Cancer League, the Swiss National Science Foundation and Cancer Research UK, were presented at the annual meeting of the American Society of Clinical Oncology (ASCO), held June 2 – 6, 2023, in Chicago, Illinois.

Recent studies have shown that aggressive chemoimmunotherapy regimens alone, such as DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) can provide excellent results without the use of radiation therapy. Additionally, novel immunotherapies, including checkpoint inhibitors and CAR-T cell therapies, are showing promise in patients with lymphoma that comes back after treatment.

Findings
The study found that patients in complete remission had a 99% overall survival rate at 30 months from randomization, regardless of whether they received radiotherapy. The additional benefit of radiotherapy in reducing the risk of relapse was minimal, with very similar progression-free survival rates observed in both groups of patients.

Induction chemoimmunotherapy was completed and response assessed in 530 patients; 268 (50.6%) had a CMR and were randomly allocated to observation (132) or radiation (136).  Median follow-up time was 63 months (interquartile range, 48-69). Progression-free survival at 30 months was 98.5% in the radiation arm and 96.2% in the observation arm.

The most common side effects of the standard chemoimmunotherapy were hair loss, fatigue, sore mouth and throat, transient reduction of the number of white blood cells (with subsequent risk of infection), platelets (with risk of bruising and bleeding), and red blood cells (anemia). Radiation treatment may lead to heart problems that include ischemic heart disease, high blood pressure, valve problems, and scarring or inflammation of the heart tissue. Radiation fields involving the lung can lead to scar tissue (fibrosis) or inflammation (pneumonitis), and restrictive or obstructive lung disease.

“The need to maximize cure rates with initial therapy has made consolidation radiotherapy a historical standard of care, based on the poor results obtained with chemotherapy alone before rituximab and the excellent results shown in trials in which almost all patients underwent irradiation,” said Emanuele Zucca, MD, consultant and head of the Lymphoma Unit at the Oncology Institute of Southern Switzerland in Bellinzona, Switzerland.

“However, the long-term toxicities of mediastinal radiotherapy are well documented, particularly second breast, thyroid, and lung cancers and increased risk of coronary or valvular heart disease, in a patient group dominated by young adults. This study shows chemoimmunotherapy alone is an effective treatment for primary mediastinal B-cell lymphoma and strongly supports omitting radiotherapy without impacting chances of cure,” Zucca added.

Next Steps
Researchers are currently exploring the feasibility of a new study to test whether using ctDNA (liquid biopsy) together with PET scans can help drive appropriate treatment decisions in patients who do not have a complete response with initial immunochemotherapy.

Clinical trial
Randomized, Open-label, Two-arms, Phase III Comparative Study Assessing the Role of Involved Mediastinal Radiotherapy After Rituximab Containing Chemotherapy Regimens to Patients With Newly Diagnosed Primary Mediastinal Large B-Cell Lymphoma – NCT01599559.

Reference
[1] How I Treat In Brief: Primary Mediastinal B-Cell Lymphoma. ASH Clinical News, November 2019. Online. Last accesses on June 3, 2023.
[2] Zucca E, Davies A, Kryachok I, Ciccone G, Ceriani L, Botto B, Mikhaeel NG, Dabrowska-Iwanicka A, et al. Observation vs. radiotherapy in primary mediastinal B-cell lymphoma patients with complete response to standard immunochemotherapy: The IELSG37 randomized trial. J Clin Oncol 41, 2023 (suppl 17; abstr LBA7505). DOI 10.1200/JCO.2023.41.17_suppl.LBA7505.

Featured image: American Society of Clinical Oncology (ASCO), held June 2 – 6, 2023, in the McCormick Place, Chicago, Illinois. Photo courtesy: © 2023 ASCO/Nick Agro. Used with permission.

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