ASCO Perspective

“These findings are particularly important for this aggressive type of lymphoma, which occurs more often in young adults. These reassuring data demonstrate that patients with primary B-cell lymphoma who have a rapid response to initial dose-intensive chemoimmunotherapy have excellent outcomes with a very low likelihood of the cancer coming back, regardless of whether they receive consolidative radiation therapy as part of their treatment. This means that these patients can safely forgo radiation and its side effects without compromising survival,” said Corey W. Speers, MD, PhD, ASCO Expert.

ALEXANDRIA, Va. — Results from the largest prospective study of primary mediastinal B-cell lymphoma show that radiation therapy can be omitted in patients who have a complete metabolic response after chemoimmunotherapy. The IELSG37 international study found that these patients may be spared from late toxicities without compromising the chances of cure. The research will be presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

Study at a Glance

Key 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.”

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, such as checkpoint inhibitors and CAR-T cell therapy, are showing promise in patients with lymphoma that comes back after treatment.

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.

The study was funded by the Swiss Cancer League and Cancer Research UK; the Swiss National Science Foundation partially supported the study in Switzerland.

View the full embargoed abstract:

LBA7505: Observation vs. radiotherapy in primary mediastinal B-cell lymphoma patients with complete response to standard immunochemotherapy: The IELSG37 randomized trial.  

Authors: Emanuele Zucca, Andrew Davies, Irina Kryachok, Giovannino Ciccone, Luca Ceriani, Barbara Botto, N George Mikhaeel, Anna Dabrowska-Iwanicka, Weili Zhao, Codruta Inescu, Andrea Janikova, Alexander Fossa, David Hodgson, Mats Jerkeman, Monica Balzarotti, Alessandra Tucci, Umberto Ricardi, Sally Barrington, Peter W. M. Johnson, Maurizio Martelli; Institute of Oncology Research; Clinic of Hematology, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale; Faculty of Biomedical Science, Universita’ della Svizzera italiana; International Extranodal Lymphoma Study Group (IELSG), Bellinzona, Lugano, Switzerland; Southampton Experimental Cancer Medicines Centre, University of Southampton, Southampton, United Kingdom; National Cancer Institute, Kiev, Ukraine; Cancer Epidemiology Unit, CeRMS and CPO Piemonte, Città della Salute e della Scienza, University of Torino, Torino, Italy; Imaging Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; AOU Citta' della Salute e della Scienza di Torino, Torino, Italy; Guy's Cancer Centre, Guy's & St Thomas' NHS Trust and King's College University, London, United Kingdom; Maria Sklodowska-Curie National Research Institute of Oncology, Warszawa, Poland; Rui Jin Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China; Inselspital, Bern, Switzerland; University Hospital Brno, Brno, Czech Republic; Oslo University Hospital, Oslo, Norway; Princess Margaret Hospital, Toronto, ON; Lund University Hospital, Lund, Sweden; IRCCS Humanitas Research Hospital, Rozzano Milano, Italy; ASST Spedali Civili di Brescia, Brescia, Italy; University of Turin, Department of Oncology, Torino, Italy; King's College London, London, United Kingdom; University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; Università La Sapienza Policlinico Umberto I, Roma, Italy  

Background: Primary mediastinal B-cell lymphoma (PMBCL) has a good prognosis if remission is rapidly achieved with dose‐intensive immunochemotherapy. In these patients mediastinal radiotherapy (RT) may consolidate responses; however, it increases the risk of second malignancies and coronary or valvular heart disease. The IELSG37 trial was planned with a non-inferiority design to test whether RT can be omitted in patients who achieve a complete metabolic response (CMR) after immunochemotherapy.  Methods: Patients with newly diagnosed PMBCL were eligible. Initial rituximab and anthracycline-based therapy was chosen according to local practice. CMR was defined, upon central review of positron emission computed tomography (PET/CT) scans, as Deauville score 1 to 3, according to the Lugano classification. Responding patients were randomized to observation (OBS) or consolidation RT (30 Gy). Randomization was stratified on gender, chemotherapy regimen, country, and PET/CT score. The primary endpoint was progression-free survival (PFS) after randomization. The sample size (540 patients to enrol, and 376 to randomize) was calculated assuming a 30-month PFS probability of 0.85 in both arms, with alpha at 0.05, 80% power and a hazard ratio (HR) of 1.77 as non-inferiority margin.  Results: At a median follow-up of 30 months, the number of observed events was considerably lower than expected, hence, the Independent Data Monitoring Committee (IDMC) of the trial recommended to complete the planned total accrual without increasing the study size or duration. The primary endpoint analysis was performed, according to the IDMC recommendation, with ≥80% of patients having a minimum follow-up of 30 months. 545 patients (209 men, 336 women) were enrolled. Induction immunochemotherapy was completed and response assessed in 530 patients, 268 of them (50.6%) achieved a CMR and were randomly allocated to OBS (n = 132) or RT (n = 136). The PFS at 30 months was 98.5% (95%CI, 94.3 – 99.6) in the RT arm and 96.2% (95%CI, 91.1-98.4) in the OBS arm (P = 0.278). The estimated relative effect of radiotherapy vs observation in terms of hazard ratio (HR) was 0.47 (0.12-1.89) without adjustments and 0.79 (0.19-3.31) after stratification for the variables used for randomization. At 30 months the absolute risk reduction from RT was 2.3% (-1.5 to 6.2) unadjusted, and 0.8% (-3.0 to 8.3) with stratified HR. The number needed to treat is high (43 patients, unadjusted, and 126 after stratification). The 5-year overall survival was 99% in both arms. Longer follow-up is needed to examine late toxicity.  Conclusions: This study is the largest prospective study of PMBCL ever conducted and although the event rate did not reach the assumed level, its evidence supports the omission of RT in patients achieving a CMR after immunochemotherapy.  

View disclosures for:

• Authors – in the abstract (will be available on May 30)
• ASCO Cancer Communications Committee 
• Dr. Speers
• Dr. Gralow

For your readers:

• Non-Hodgkin Lymphoma

ATTRIBUTION TO THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY ANNUAL MEETING IS REQUESTED IN ALL COVERAGE.

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