Mediastinal Radiotherapy May be Safely Omitted Following Frontline Immunochemotherapy in PMBCL

Emanuele Zucca, MD

For patients with primary mediastinal B-cell lymphoma (PMBCL) who achieve complete mediated responses following frontline immunochemotherapy, maintenance radiotherapy (RT) may be safely omitted in favor of observation, according to findings from the phase 3 IELSG37 trial (NCT01599559), which were presented at the 2023 ASCO Annual Meeting. These findings are in line with the results of single-institution retrospective studies, although investigators noted that longer follow-up is still needed to evaluate long-term toxicities.¹

The 30-month overall survival (OS) rate was 99.2% (95% CI, 94.7%-99.9%) among those randomly assigned to undergo observation (n = 132) vs 99.3% (95% CI, 94.9%-99.9%) among those randomly assigned to RT (n = 136; P = .601). The progression-free survival (PFS) rate at 30 months was 96.2% (95% CI, 91.1-98.4) with observation and 98.5% (95% CI, 94.2%-99.6%) with radiotherapy (P = .274).¹

Of note, this was translated to an unadjusted HR of 0.47 (95% CI, 0.12-1.88) for a relative effect of RT compared with observation on PFS. The stratified HR was 0.68 (95% CI, 0.16-2.91). Moreover, the absolute difference between RT and observation was 2.3% in an unadjusted analysis (95% CI, –1.5 to 6.2). The stratified absolute difference was 1.2% (95% CI, –3.2 to 7.0).¹

“The OS was nearly identical—over 99% in both arms,” Emanuele Zucca, MD, a medical oncologist at the Oncology Institute of Southern Switzerland, said in a presentation of the findings. “Thus far, few late [toxicity] events ever already been described, nevertheless, all of them are affecting patients allocated to radiotherapy.”¹

As Zucca explained in his presentation, the decision to treat patients with radiotherapy for PMBCL remains a controversial one.1 He stated that the disease is largely curable, but patients who do not achieve complete remission face poor prognosis, thus many cancer centers feel pressure to use irradiation. In 2016, Jackson et al published findings which demonstrated that patients who received combined modality therapy (systemic therapy plus RT) achieved superior 5-year OS outcomes than patients who received systemic therapy alone (93% vs 83%, respectively).² However, in 2013, findings which were published in the New England Journal of Medicine showed that at a median follow-up of 63 months, patients who received DA-EPOCH-R (dose-adjusted etoposide phosphate, prednisone, vincristine sulfate [Oncovin], cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), and rituximab [Rituxan]) and no RT, achieved an OS rate of 97%. Study investigators therefore argued that patients do not require radiotherapy following treatment with intensive regimens.³

Thus, investigators sought to evaluate whether mediastinal irradiation could be safely omitted in patients who achieve complete responses following conventional rituximab plus chemotherapy.¹ The primary end point of this study was PFS in patients who were PET-negative 30 months post randomization. The secondary end points included 5-year OS rates and long-term toxicities.¹

The trial was designed to test noninferiority. Upon registration, patients underwent a baseline PET/CT. They then proceeded to receive standard immunochemotherapy. Selections included rituximab-containing regimens such as R-CHOP21 (rituximab cyclophosphamide, doxorubicin, vincristine, prednisolone), R-CHOP14, R-CHOEP (R-CHOP plus etoposide), DA-EPOCH-R (etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, hydroxydaunorubicon, and rituximab), or rituximab with MACOP-B (methotrexate, leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin) or VACOP-B (etoposide, leucoviorin, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin).¹

At the end of therapy, patients underwent PET/CT with central review. If patients were PET positive (Deauville Score [DS] 4-5) they received salvage therapy. Patients who were PET negative (DS, 1-3) were randomly assigned to either undergo mediastinal RT at 30 Gy within 8 weeks of completing rituximab-based chemotherapy, or observation. Ultimately, 545 patients were enrolled, 430 underwent central PET review, and 268 were PET-negative, and therefore eligible to be assigned to one of the treatment arms.¹

In both arms, the median age was 35.5 years (IQR, 29-46.5). Most patients were women (65% vs 63%) in both the RT and observation groups. Most patients had an ECOG performance status of 0 (54% vs 52%) or 1 (37% vs 41%), had bulky disease (65% vs 60%), elevated lactate dehydrogenase (67% vs 67%), and were considered intermediate risk using the Revised International Prognostic Index score (72% vs 73%). At the end of frontline therapy, most patients also had a DS score of 2 (52% vs 51%) in both arms.¹

The median follow-up for patients in the observation arm was 58.8 months (95% CI, 55.8-59.8) and was 58.8 months (95% CI, 54.4-60.6) in the RT arm.¹

Among patients who were randomly assigned to RT, 3 severe cardiac events and 3 secondary cancers were reported. These patients had been in continuous complete response at their last PMBCL visit.¹

There was 1 case of left ventricular systolic dysfunction that occurred in a patient who was assigned to RT. The event occurred during chemotherapy and was resolved. One patient experienced both grade 4 acute heart failure and grade 3 hypertension. This patient was receiving RT and experienced these events 18, and 8 months, respectively, from randomization. Both cases were resolved. There was 1 case of grade 4 metastatic melanoma, which occurred in a patient on the RT arm. This occurred 22 months following randomization and resulted in a death from concurrent sepsis.¹

There was 1 case of grade 3 glioblastoma on a patient in the RT arm. This occurred 55 months after randomization and resulted in death. Additionally, 1 patient on the RT arm developed acute myeloid leukemia 15 months post randomization. This patient achieved a complete response after allogeneic transplant.¹

“The takeaway message is that this study is the largest trial ever conducted in this disease, and [that] mediastinal radiotherapy may be safely omitted in patients with complete metabolic response after frontline immunochemotherapy with rituximab and doxorubicin,” Zucca concluded.¹

References

1. Zucca E, Davies A, Kryachock I, et al. Observation vs radiotherapy in primary mediastinal B-cell lymphoma (PMBCL) patients with complete responses to standard immunochemotherapy: the IELSG37 randomized trial (NCT01599559). J Clin Oncol. 2023;41(suppl 17):7505. doi:10.1200/JCO.2023.41.17_suppl.LBA7505
2. Jackson MW, Rusthoven CG, Jones BL, Kamdar M, Rabinovitch R. Improved survival with combined modality therapy in the modern era for primary mediastinal B-cell lymphoma. Am J Hematol. 2016;91(5):476-480. doi:10.1002/ajh.24325
3. Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med. 2013;368(15):1408-1416. doi:10.1056/NEJMoa1214561