Real-world data analysis of survival outcomes of patients with primary mediastinal large B- cell lymphoma treated with upfront consolidative radiation therapy following immunochemotherapy

doi:10.21203/rs.3.rs-5011154/v1

Background

Primary mediastinal large B-cell lymphoma (PMBCL) is a rare subtype of diffuse large B-cell lymphoma. PMBCL predominantly affects young adults and survival outcomes are favorable. Radiation therapy (RT) has been included in the primary treatment option for PMBCL, but intensified immunochemotherapy has raised doubts about this strategy. This study aimed to explore the role of consolidative RT in the primary treatment of PMBCL.

Methods

This single-center study retrospectively analyzed the survival outcomes of 65 newly diagnosed PMBCL patients. All 65 patients received rituximab-containing therapy. Patients in this study were divided into three groups based on their primary treatment: (1) EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) (n = 7), (2) R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) only (R-CHOP group, n = 31, and (3) R-CHOP with consolidative RT (R-CHOP + RT group, n = 27).

Results

The estimated objective response rates and complete remission rates for all patients were 86.2% and 63.1%, respectively. Median 3-year progression-free survival (PFS) and overall survival (OS) rates were 72% and 81%, respectively. All patients in the R-CHOP + RT group achieved an objective response, with a complete remission rates of 59.3%. The R-CHOP + RT group demonstrated better PFS compared to those who did not receive consolidative RT (p = 0.028), although there was no significant difference in OS (p = 0.102). In particular, consolidative RT conferred a survival benefit to patients with initial bulky disease or those who had an insufficient end-of-treatment response. The predictive value of ¹⁸F-fluorodeoxyglucose positron-emission tomography-computed tomography (PET-CT) in assessing treatment response in PMBCL was revalidated, showing that patients who achieved a negative end-of-treatment PET-CT had significantly better survival outcomes than those who did not. One-fourth of the patients experienced disease relapse, and only 30% achieved long-term lymphoma control. The immune checkpoint inhibitor exhibited modest efficacy in this study.

Conclusions

R-CHOP is a useful alternative regimen when intensified chemotherapy is not feasible and consolidative RT should be considered in cases of initial bulky disease and insufficient end-of-treatment response.

primary mediastinal large B-cell lymphoma

front-line treatment

radiation therapy

Primary mediastinal large B-cell lymphoma (PMBCL) is a rare subtype of diffuse large B-cell lymphoma (DLBCL) involving transformed thymic B-cells that mainly affects the mediastinum. PMBCL has distinct features that set it apart from DLBCL. Clinical and molecular characteristics of PMBCL resemble those of Hodgkin lymphoma, such as activation of the JAK-STAT and NF-kB pathways, downregulation of MHC class I and II, as well as upregulation of programmed death ligands (PD-L) [1–3]. Due to the low incidence of less than 5% of all non-Hodgkin lymphomas (NHLs), clinical management strategies and treatment outcome prediction for PMBCL have been predominantly extrapolated from those used in DLBCL [4–6]. Based on the accumulated data, front-line systemic treatment of PMBCL comprises CD20-targeted monoclonal antibody (e.g. rituximab) and anthracycline-containing regimens, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), EPOCH (etoposide, cyclophosphamide, doxorubicin, vincristine, and prednisone) and M/VACOP-B (etoposide or methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin) [7, 8]. The 5-year progression-free survival (PFS) rates of these regimens have been reported as 78–81%, 87–93%, and 84%, respectively [3]. Despite these potent systemic treatments, residual density makes it challenging to distinguish between fibrotic tissue and active lymphoma, and consolidative treatment is frequently required [4].

Considering the radiosensitive nature of PMBCL, implementation of upfront consolidative radiation therapy (RT) following front-line immunochemotherapy has significantly decreased primary site relapse [4, 9, 10], making it a widely adopted practice. ¹⁸F-fluorodeoxyglucose positron-emission tomography-computed tomography (FDG PET-CT)-guided Lugano response assessment has emerged as an innovative methodology to identify patients eligible for the omission of consolidative RT. Consequently, consolidative RT is recommended for PBMCL patients who did not achieve complete remission (CR) as determined by PET-CT after front-line systemic treatment [11, 12]. In addition, the introduction of various intensified immunochemotherapy regimens has undervalued the efficacy of consolidative RT [13, 14]. The absence of comparative analysis data within the confines of identical treatment protocols underscores the need for circumspection when evaluating the efficacy of consolidative RT.

We conducted a retrospective analysis to assess treatment outcomes utilizing PET-CT after upfront consolidative RT following immunochemotherapy containing rituximab. Through real-world data analysis, we evaluated the clinical outcomes of newly diagnosed PMBCL (ND-PMBCL) patients treated with the standard therapeutic strategy, and explored patient characteristics guiding the decision to perform or omit consolidative RT. Additionally, we analyzed the survival outcomes of subsequent treatments in patients with relapsed or refractory PMBCL (RR-PMBCL).

Study overview

Since 2017, we identified 65 ND-PMBCL patients from prospective cohort studies conducted at Samsung Medical Center [institutional review board (IRB) number: 2022-05-078]. All patients were pathologically diagnosed with PMBCL by two lymphoma pathologists (J.C. and Y.H.K.) based on immunohistochemistry results in accordance with WHO diagnostic criteria [15]. The study registration of patients concluded in January 2022 and data analysis was based on information available up to June 2023, which served as the cutoff date for this study. The IRB of Samsung Medical Center approved this study (approval number. 2016-11-040-025), and written informed consent was obtained from each patient prior to their study enrollment. This study was conducted under the ethical principles of the Declaration of Helsinki and the Korea Good Clinical Practice guidelines.

The following clinical and laboratory data were collected by medical record review: age; sex; Eastern Cooperative Oncology Group Performance status; presence of B symptoms; presence of extra-nodal involvement, bone marrow (BM) involvement, pleural or pericardial involvement; presence of superior vena cava (SVC) syndrome; presence of a bulky mass (≥ 10 cm); Ann Arbor stage; International Prognostic Index (IPI); complete blood count; lactate dehydrogenase level; C-reactive protein level; erythrocyte sedimentation rate; and β-2 microglobulin level.

Primary treatment

Front-line immunochemotherapy regimen consisted of R-CHOP (rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², vincristine 1.4 mg/m², and prednisone 40 mg/m²) and EPOCH-R (etoposide 50 mg/m², prednisone 60 mg/m², vincristine 0.4 mg/m², cyclophosphamide 750 mg/m², doxorubicin 10 mg/m², and rituximab 375 mg/m²). Notably, due to reimbursement from the National Health Insurance in Korea, the majority of patients in this study (n = 58, 89.2%) opted for R-CHOP as their front-line regimen (Fig. 1). Treatment response was evaluated every three cycles of front-line treatment, using the Lugano classification for lymphoma, which is based on PET-CT. FDG uptake degree was visually quantified according to the 5-point Deauville scale (DS) [16, 17]. In this study, PET-CT results were designated as follows: DS 1, 2, and 3 were interpreted as negative findings, while DS 4 and 5 were considered positive.

After front-line treatment was completed, consolidative RT was performed according to the combined decision of a hematologist and a radiologist. Based on the end-of-treatment (EOT) response assessment, upfront consolidative RT was recommended for patients who achieved less than partial response (PR) and those who achieved CR but initially showed a bulky mass. Finally, consolidative RT was decided after sufficient discussion with the patient about the risks and benefits. RT was initiated two to four weeks following the final cycle of front-line treatment, with a median total dose of 36 grays (range, 24–40 grays), delivered to the involved-field with 1.8-2.0 grays/fraction, five times per week, over a period of three to four weeks.

Subsequent treatment

Patients who failed primary treatment were subsequently treated with various systemic therapies. Choice of subsequent therapy among the following regimens was determined based on the physician's discretion and institutional protocols: platinum-containing chemotherapies [DHAP (dexamethasone, cytarabine, and cisplatin), ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin), GDP (gemcitabine, dexamethasone, and cisplatin), ICE (ifosfamide, carboplatin, and etoposide)] with or without rituximab, lenalidomide plus rituximab, polatuzumab plus BR (bendamustine, and rituximab), brentuximab vedotin, or immune checkpoint inhibitors (ICIs) such as pembrolizumab and nivolumab. Following salvage treatment, autologous stem cell transplantation (ASCT) was considered based on the patient's condition and disease status.

Statistical analysis

Descriptive statistics are presented as percentages and medians, and intergroup comparisons of categorical variables were conducted using the χ² test or Fisher's exact test. Objective response rate (ORR) was defined as the proportion of patients who achieved a CR or PR with their best responses obtained during treatment. CR was defined as a DS of 1, 2, or 3 in nodal or extranodal sites, while PR was defined as a DS of 4. Kaplan-Meier method was used to estimate overall survival (OS) and PFS. OS was assessed from diagnosis to death or the last follow-up date; PFS was estimated from diagnosis to disease progression or death from any cause. To elucidate factors associated with survival outcomes following a diagnosis of PMBCL, we performed univariate and multivariate analyses using Cox proportional hazards models. All data were analyzed using the Statistical Package for Social Sciences software, version 24.0 (IBM Corp., Armonk, NY, USA).

Patient characteristics

Baseline demographics of the 65 ND-PMBCL patients at diagnosis are presented in Table 1. Median patient age was 32 years (range, 16-86 years). Fifty-two percent of patients (80.0%) were diagnosed with PMBCL before the age of 40. There were more female patients (n=35, 58.5%) than male patients (n=27, 41.5%). At diagnosis, 35% of patients (n=23) showed extra-nodal lymphoma involvement, while BM infiltration was infrequent (n=2, 3.1%). PMBCL invaded the pleura (n=7, 10.8%) or pericardium (n=9, 13.8%), while SVC syndrome with a bulky mass was observed in 10.8% (n=7) of patients. More than half of the patients (n=34, 52.3%) included in this study had advanced disease (stage III or IV). Nevertheless, the IPI classified approximately 85% of patients (n=55) as low or low/intermediate risk.

Patients in this study were divided into three groups based on their primary treatment: (1) EPOCH-R (n=7, 10.7%), (2) R-CHOP only (R-CHOP group, n=31, 47.7%), and (3) R-CHOP with consolidative RT (R-CHOP + RT group, n=27, 41.5%) (Fig. 1). Patients in the EPOCH-R group did not receive any consolidative radiotherapy. Median number of front-line immunochemotherapy cycles administered to patients in each group was 6 (range, 1-6), 6 (range, 3-6), and 6 (range, 6-8), respectively. There were not significant differences in baseline demographics among the three groups (Table 1).

Primary treatment for ND-PMBCL

Based on the best response, the estimated ORR and CR achievement rates for all patients were 86.2% (n=56) and 63.1% (n=41), respectively (Fig. 2a). The EPOCH-R group achieved an ORR of 42.9% (3/7) and a CR rate of 28.6% (2/7). The R-CHOP group achieved an ORR of 83.9% (26/31) and a CR rate of 74.2% (23/31). All patients in the R-CHOP + RT group showed an objective response (n=27, 100%), with a CR rate of 59.3% (16/27). ORR achievement rates were significantly different among the three primary treatment groups (p<0.001), whereas there were no significant differences in CR achievement rates among groups (p=0.067) (Fig. 2b).

With a median follow-up duration of 35.7 months, PFS and OS did not reach the median value, and the estimated median 3-year PFS and OS for primary treatment were 72% and 81%, respectively (Fig. 2c, d). In PFS analysis, survival curves according to the primary treatment were clearly distinguishable, with the EPOCH-R group [6.0 months, 95% confidence interval (CI) 0.868 - 11.132] showing a significantly worse outcome than the R-CHOP group [median survival not reached (NR)] and R-CHOP + RT group (median survival NR) (Fig. 2e). The R-CHOP + RT group (median survival NR) had a more favorable median OS than the R-CHOP (median survival NR) and EPOCH-R groups (30.5 months, 95% CI, 25.284 - 35.716) (Fig. 2f). In particular, patients with bulky disease at diagnosis (n=8) showed a trend towards improved survivals when receiving consolidative RT, although this was not statistically significant (Fig. 2g, h).

We performed Cox regression analysis to identify factors predicting better survival outcomes with primary treatment. Inclusion of consolidative RT in the primary treatment (hazard ratio 0.81, 95% CI, 0.016-0.411, p=0.002) and negative EOT PET-CT findings (hazard ratio 9.843, 95% CI, 1.414-68.496, p=0.021) were associated with improved PFS. However, we did not identify any clinical factors that significantly affected OS (Table 2).

Survival outcomes according to response evaluation with PET-CT

Of the 58 patients uniformly treated with front-line R-CHOP therapy (Fig. 3a), 39 (67.2%) exhibited negative PET-CT findings (DS 1 to 3), while the remaining 19 (32.8%) did not (DS 4 or 5) during the interim evaluation. After completing front-line treatment, 44 patients (75.9%) achieved negative PET-CT results (Fig. 3b). Most patients (37/39, 94.9%) who obtained negative PET-CT in the interim evaluation also maintained their PET-CT negativity in the EOT assessment. By contrast, approximately 37% of patients (n=7/19) with positive PET-CT in the interim evaluation acquired PET-CT negativity in the EOT assessment (Fig. 3b). During the interim evaluation, 71% (22/31) of the R-CHOP group and 63% (17/27) of the R-CHOP + RT group achieved PET-CT negativity. At the EOT evaluation, 80.6% (25/31) of the R-CHOP group had negative PET-CT findings, while 70.3% (19/27) of the R-CHOP + RT group had negative findings. There were no significant differences in interim (p=0.517) or EOT PET-CT (p=0.362) results between the R-CHOP and R-CHOP + RT groups (Fig. 3c).

Achievement of negative interim PET-CT findings correlated with significantly better survival outcomes, whereas failure to achieve negative PET-CT findings during the interim evaluation was associated with suboptimal survival outcomes (Fig. 3d, e). Additionally, regardless of interim PET-CT results, patients who acquired EOT PET-CT negativity showed significantly better survival outcomes than those who did not (Fig. 3f-i). Logistic regression analysis revealed that positive interim PET-CT findings (p<0.001) were significantly associated with positive EOT PET-CT (Table 3).

We were particularly interested in determining the role of consolidative RT based on EOT PET-CT results to define further the indications for upfront consolidative RT in patients treated with front-line R-CHOP. Patients who achieved a DS 1 or 2 on EOT PET-CT showed no difference in survival outcomes with the administration of consolidative RT. In patients with a DS of 3, which corresponded to negative PET-CT findings, administering consolidative RT tended to prolong PFS but did not result in a difference in OS. However, in those with a DS 4, consolidative RT had a significant impact on both PFS (p=0.001) and OS (p=0.001) (Fig. 3j, k).

RR-PMBCL after primary treatment failure

A total of 16 patients (24.6%) experienced disease relapse following primary treatment, all but one of whom (93.8%) had early RR-PMBCL. Disease relapse occurred in five (31.2%), nine (56.2%), and two (12.5%) patients in the EPOCH-R, R-CHOP, and R-CHOP + RT groups, respectively (p=0.002), with the R-CHOP + RT group showing a relatively lower relapse rate than the other groups (Fig. 4a). There were 11 cases (68.8%) of local relapse and five cases (31.2%) of distant relapse (Fig. 4b), with no differences observed based on primary treatment. Disease relapse adjacent to the primary site was associated with better survival outcomes than relapses at distant sites (Fig. 4c). Approximately 60% of patients (11/18) with positive EOT PET-CT had disease relapse, while only 10% of patients (5/47) with negative EOT PET-CT relapsed (Fig. 4d). The estimated median OS for RR-PMBCL was 21.9 months (95% CI, 0.2–43.7 months) (Fig. 4e).

All relapsed patients received various types of subsequent treatments. Due to the small number of patients allocated to each salvage treatment, comparing the efficacy of these salvage treatments was challenging. In this study, a notable proportion (75.0%, 12/16) received ICIs, including pembrolizumab (n=11) and nivolumab (n=1). Prior to receiving ICI therapy, the patients underwent a median of 3 (range, 1-6) lines of treatment. Median number of cycles of ICI therapy was 3 (range, 1-24), with a median treatment duration of 2.2 months. The ORR of ICI therapy was 58.3% (n=7), and a quarter of patients obtained CR (n=3). Two patients (Pt.1, 2) who obtained CR discontinued treatment after seven months and two years of pembrolizumab therapy, respectively. Another patient (Pt.3) underwent consolidative ASCT after obtaining CR with six months of pembrolizumab therapy. These three patients remained alive without disease progression until the cutoff date (Fig. 4f). Despite the ICI therapy, two-thirds of patients (66.6%, 8/12) experienced disease progression eventually. The 1-year PFS and OS for ICI therapy were 20% and 54%, respectively. During ICI therapy, no instances of treatment discontinuation, dose reduction, or mortality due to adverse effects were observed.

Several earlier studies of PMBCL have consistently demonstrated the efficacy of rituximab-containing immunochemotherapy; however, due to heterogeneous front-line regimens and RT indications, as well as varying protocols, a uniform conclusion regarding the role of consolidative RT has not been reached (Table 4). In this study, we evaluated the role of upfront consolidative RT following front-line immunochemotherapy in ND-PMBCL patients. Integration of consolidative RT into the primary treatment yielded clinical benefits with limited adverse events in this study. Patients who received the R-CHOP as front-line treatment and underwent consolidative RT had a prolonged PFS and potentially reduced risk of disease relapse. Unfortunately, inclusion of consolidative RT in the primary treatment did not result in an extension of OS.

As demonstrated by a recent large prospective study [18], omission of consolidative RT in PMBCL patients is advocated, particularly in patients who have received intensive front-line immunochemotherapy or attained a complete metabolic response (DS of 1 to 3) on EOT PET-CT. In support of this, we found that consolidative RT did not yield significant benefits for patients with DS 1 or 2 on EOT PET-CT in this study. Among patients with a DS of 3 who had indeterminate FDG uptake, consolidative RT was associated with a trend of improved survival, although this association was not statistically significant. Conversely, RT provided significant survival benefits for patients with a DS of 4 (Fig. 3j, k). Patients who received consolidative RT had numerically lower rates of both local and distant relapse than those who did not (Fig. 4a, b). This significant reduction in the overall relapse rate appears to have led to an extension of PFS. In previous studies, consolidative RT demonstrated sufficient survival benefits alongside manageable toxicity [9, 10]. Although recently introduced intensified front-line immunochemotherapy has diluted the role of consolidative RT, it remains a valid option for patients meeting specific conditions. Data from Asian study supports the implementation of consolidative RT following R-CHOP induction in patients with ND-PMBCL who present with bulky disease [19]. Despite the limitation of a small sample size (n=8), our study also demonstrated that patients with initial bulky disease had a trend towards better survivals when receiving consolidative RT than those who did not. Consequently, we advocate the use of consolidative RT in patients receiving front-line R-CHOP therapy who have remnant lesions indicating DS of 4 on EOT PET-CT or initial bulky disease.

Three primary treatment strategies incorporating standard immunochemotherapy regimens were evaluated in this study: EPOCH-R, R-CHOP only, and R-CHOP combined with RT. At a glance, the clinical outcomes with EPOCH-R appeared somewhat disappointing compared to the other two treatments; however, a direct comparison of the front-line regimen's efficacy was challenging for several reasons. First, the limited number of patients (n=7, 10.8%) treated with EPOCH-R hindered comprehensive evaluation. Second, there was significant heterogeneity in the baseline characteristics of the patients, with a notable tendency of those with deteriorated disease status to be treated with the EPOCH-R regimen (Table 1). According to previous studies (Table 4), favorable outcomes have been reported for EPOCH-R therapy as an intensive chemotherapy, and mediastinal RT can be safely omitted when using this treatment [13, 20-22]. However, treatment-related hematologic toxicities are prevalent in patients treated with EPOCH-R. Thus, relatively older and frail PMBCL patients might not be suitable candidates for intensive immunochemotherapy as their primary treatment. In the comparative study by Nirav et al. of R-CHOP versus dose-adjusted R-EPOCH (DA-R-EPOCH) as front-line management strategies for PMBCL [23], patients receiving DA-R-EPOCH had higher CR rates (84% vs. 70%, p=0.046) but were more likely to experience treatment-related toxicities. Therefore, R-CHOP therapy could be an excellent alternative for PMBCL patient populations who are frail and expected to have poor performance.

Conventionally, FDG PET-CT has been widely used to evaluate the response of lymphoma after immunochemotherapy. Similarly, in PMBCL, PET-CT generally has an excellent negative predictive value [18]; however, post-treatment inflammatory remnant tissue often results in false-positive PET-CT findings, raising concerns about a low positive predictive value [13, 21]. We reaffirmed that PET-CT is a suitable tool for assessing treatment response in PMBCL; in particular, survival outcomes were better when PET-CT negativity was achieved early (Fig. 3d-g). Additionally, PET-CT assists in identifying patients who would benefit from consolidative RT after primary treatment (Fig. 3j, k). Recently, to overcome the limitations of the 5-point DS based on visual interpretation of FDG uptake, quantitative evaluation methods using total lesion glycolysis have been introduced and have been demonstrated to have better predictive value [24, 25]. Moreover, monitoring circulating tumor DNA could enhance the evaluation of therapeutic response, allow accurate identification of false-positive PET-CT results caused by residual mediastinal uptake, and determine which patients would benefit from consolidative RT [26, 27]. We expect that advancements in EOT evaluation modalities will clarify the role and indications of consolidative RT in PMBCL in the near future.

Although patients with PMBCL generally have better survival outcomes than those with conventional DLBCL [4], treatment failure is not uncommon and often occurs early after primary treatment completion [28, 29]. In this study, approximately a quarter of patients experienced primary treatment failure, with most experiencing early relapse. Local disease relapses were more common than distant relapses (Fig. 4b), and patients with local relapse showed better survival outcomes (Fig. 4c). In cases of RR-PMBCL, approximately 30% achieved a long-term response through various salvage therapies, consistent with findings from other studies. Systemic treatment followed by high-dose chemotherapy and ASCT remain the mainstays of salvage treatment. However, although these treatment strategies are particularly beneficial for some chemo-sensitive patients, they have overall inadequate long-term efficacy [30, 31]. Thus, there is a need for alternative treatment approaches that incorporate the molecular or genetic characteristics of PMBCL. In particular, frequently found genetic alterations at the 9p24.1 locus are associated with the overexpression of PD-L1, thus ICIs may be effective against PMBCL. Indeed, based on the efficacy and safety of pembrolizumab in the phase 1B KEYNOTE-013 trial and the phase 2 KEYNOTE-170 trial, this ICI has been approved by the FDA for the treatment of R/R PMBCL [32, 33]. However, real-world experience of ICI therapy in PMBCL is limited, and existing studies suggest that ICI therapy has modest efficacy. We evaluated the use of ICI in RR-PMBCL in the current study; unfortunately, the efficacy of ICI was moderate at best. Furthermore, biomarkers to predict the response need to be determined (Table 5). Recent significant advancements and successes in cellular therapy have substantially expanded the treatment options for RR-PMBCL [34-37]. Nevertheless, there is currently no consensus on the optimal therapy for RR-PMBCL, highlighting the need for research into the sequence of salvage treatments and appropriate treatment selection based on patient characteristics and disease nature.

In conclusion, we demonstrated the efficacy of front-line R-CHOP therapy in ND-PMBCL patients and our findings support the proactive implementation of consolidative RT in patients with initial bulky disease or DS 4 lesions on EOT PET-CT. The poor prognosis of patients with RR-PMBCL was reaffirmed in this study. Although ICI may be an option for salvage treatment, its efficacy remains suboptimal. Various efforts are being made to improve survival outcomes in RR-PMBCL; where feasible, the proactive application of cellular therapies, such as chimeric antigen receptor T-cell therapy, is warranted.

PMBCL: Primary mediastinal large B-cell lymphoma; DLBCL: Diffuse large B-cell lymphoma; NHL: Non-Hodgkin lymphoma; ND-PMBCL: Newly diagnosed primary mediastinal large B-cell lymphoma; RR-PMBCL: relapsed or refractory primary mediastinal large B-cell lymphoma; CHOP: Ccyclophosphamide, doxorubicin, vincristine, and prednisone; EPOCH: Etoposide, cyclophosphamide, doxorubicin, vincristine, and prednisone; M/VACOP-B: Eetoposide or methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin; DHAP: Dexamethasone, cytarabine, and cisplatin; ESHAP: Etoposide, methylprednisolone, cytarabine, and cisplatin; GDP: Gemcitabine, dexamethasone, and cisplatin; ICE: Ifosfamide, carboplatin, and etoposide; BR: Bendamustine, and rituximab; ICI: immune checkpoint inhibitor; DA-R-EPOCH: Dose-adjusted rituximab, etoposide, cyclophosphamide, doxorubicin, vincristine, and prednisone; RT: Radiation therapy; ASCT: autologous stem cell transplantation; FDG PET-CT: ¹⁸F-fluorodeoxyglucose positron-emission tomography-computed tomography; DS: Deauville scale; PFS: Progression-free survival; OS: Overall survival; CR: Complete remission; PR: Partial response; ORR: Objective response rate; IRB: institutional review board; BM: bone marrow; SVC: superior vena cava; IPI: International prognostic index; EOT: end-of-treatment; CI: confidence interval; NR: Not reached; PD-L: Programmed death ligands

Ethics approval and consent to participate

This study was approved by the Institutional Review Board of Samsung Medical Center (approval number: 2016-11-040-025). All patients gave written informed consent prior to study participation.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Author Contribution

Y-P.L. and S.E.Y. wrote the manuscript. Y-P.L., J.C., Y.H.K., W.S.K., S.J.K., and S.E.Y. analyzed the data. S.E.Y. reviewed the clinical data. J.C. and Y.H.K. reviewed the pathology, and S.E.Y. designed the study.

Acknowledgements

We express our gratitude to the patients who participated in this study.

Availability of data and materials

All data are available upon request to the corresponding authors.

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Table 1. Baseline demographics and disease characteristics at diagnosis.

Characteristics		Total (n=65)	R-EPOCH (n=7)	R-CHOP (n=31)	R-CHOP + RT (n=27)	*P-value
Age (years)	Median, (range)	32 (16-86)	32 (19-39)	32 (20-86)	31.5 (16-57)	0.054
	≤ 40	52 (80.0%)	7 (100.0%)	21 (%)	24 (%)
	> 40	13 (20.0%)	0 (0.0%)	10 (%)	3 (%)
Sex	Male	27 (41.5%)	3 (%)	13 (%)	11 (%)	0.927
Sex	Female	38 (58.5%)	4 (%)	18 (%)	16 (%)	0.927
ECOG-PS	0–1	54 (83.1%)	6 (%)	25 (%)	23 (%)	0.648
ECOG-PS	2–4	11 (16.9%)	1 (%)	6 (%)	4 (%)	0.648
B symptom	Present	2 (3.1%)	1 (%)	1 (%)	0 (0.0%)	0.346
LDH	Elevated	56 (86.2%)	7 (100.0%)	25 (%)	24 (%)	0.387
β2-microglobulin	Elevated	4 (6.2%)	1 (%)	1 (%)	2 (%)	0.460
CRP	Elevated	22 (33.8%)	4 (%)	6 (%)	12 (%)	0.034
ESR	Elevated	38 (58.5%)	1 (%)	22 (%)	15 (%)	0.085
Extra-nodal involvement	Absence	42 (64.6%)	1 (%)	25 (%)	16 (%)	0.200
	1 site	12 (18.5%)	3 (%)	3 (%)	6 (%)
	≥ 2 sites	11 (16.9%)	3 (%)	3 (%)	5 (%)
Bone marrow involvement	Present	2 (3.1%)	0 (0.0%)	1 (%)	1 (%)	0.921
Pleural involvement	Present	7 (10.8%)	1 (%)	3 (%)	3 (%)	0.858
Pericardial involvement	Present	9 (13.8%)	2 (%)	3 (%)	4 (%)	0.549
SVC syndrome	Present	7 (10.8%)	0 (0.0%)	3 (%)	4 (%)	0.549
CD30 expression	Present	51 (78.5%)	6 (%)	22 (%)	23 (%)	0.195
Bulky (≥10 cm) mass	Present	8 (12.3%)	0 (0.0%)	4 (%)	4 (%)	0.833
Ann Arbor stage	I/II	31 (47.7%)	1 (%)	17 (%)	13 (%)	0.611
Ann Arbor stage	III/IV	34 (52.3%)	6 (%)	14 (%)	14 (%)	0.611
IPI	Low	34 (52.3%)	1 (%)	18 (%)	15 (%)	0.206
	Low/Intermediate	21 (32.3%)	3 (%)	11 (%)	7 (%)
	High/Intermediate	9 (13.8%)	3 (%)	1 (%)	5 (%)
	High	1 (1.5%)	0 (0.0%)	1 (%)	0 (0.0%)

Abbreviations: R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; RT, radiation therapy; R-EPOCH, rituximab, etoposide, cyclophosphamide, doxorubicin, vincristine, and prednisone; ECOG-PS, eastern cooperative oncology group performance status; LDH, lactate dehydrogenase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; SVC, superior vena cava, IPI, international prognostic index

* for comparison between R-CHOP and R-CHOP + RT

Table 2. Univariate and multivariate analyses of progression-free survival and overall survival

Variables	Progression-free survival
	Univariate		Multivariate
	HR (95%CI)	*P-value*	HR (95%CI)	*P-value*
Age > 40 years	1.291 (0.342 – 4.878)	0.706	-	-
Male	1.220 (0.372 – 3.998)	0.743	-	-
ECOG-PS ≥ 2	0.036 (0.000 – 24.239)	0.317	-	-
Stage ≥ III	2.950 (0.782 – 11.126)	0.110	-	-
IPI ≥ 3	1.532 (0.331 – 7.094)	0.586	-	-
Bulky (≥10 cm) disease	1.740 (0374 – 8.103)	0.480	-	-
LDH elevated	0.829 (0.179 – 3.847)	0.811	-	-
CRP elevated	1.246 (0.453 – 3.430)	0.671
ESR elevated	0.425 (0.157 – 1.152)	0.093
Extra-nodal involvement	1.343 (0.393 – 4.591)	0.638	-	-
Pleural involvement	1.530 (0.329 – 7.110)	0.587	-	-
Pericardial involvement	0.041 (0.000 – 143.900)	0.443	-	-
SVC syndrome present	0.041 (0.000 – 105.680)	0.425	-	-
Upfront radiation therapy	0.210 (0.045 – 0.973)	0.046	0.81 (0.016 – 0.411)	0.002
Positive Interim PET-CT	6.455 (1.709 – 24.383_	0.006	2.393 (0.327 – 17.532)	0.391
Positive EOT PET-CT	7.858 (2.279 – 27.098)	0.001	9.843 (1.414 – 68.496)	0.021
Variables	Overall survival
	Univariate		Multivariate
	HR (95%CI)	*P-value*	HR (95%CI)	*P-value*
Age > 40 years	0.632 (0.074 – 5.410)	0.675	-	-
Male	1.362 (0.275 – 6.748)	0.705	-	-
ECOG-PS ≥ 2	0.037 (0.000 – 389.171)	0.486	-	-
Stage ≥ III	5.744 (0.670 – 49.227)	0.111	-	-
IPI ≥ 3	1.698 (0.198 – 14.603)	0.629	-	-
Bulky (≥10 cm) disease	3.855 (0.705 – 21.066)	0.119	-	-
LDH elevated	1.278 (0.149 – 10.969)	0.823	-	-
CRP elevated	0.961 (0.240 – 3.845)	0.955
ESR elevated	0.253 (0.063 – 1.020)	0.053
Extra-nodal involvement	2.729 (0.549 – 13.570)	0.220	-	-
Pleural involvement	1.425 (0.166 – 12.226)	0.747	-	-
Pericardial involvement	0.043 (0.000 – 190.575)	0.635	-	-
SVC syndrome present	0.042 (0.000 – 354.308)	0.583	-	-
Upfront radiation therapy	0.200 (0.023 – 1.711)	0.142	-	-
Positive Interim PET-CT	20.712 (0.085 – 488.187)	0.181
Positive EOT PET-CT	71.273 (0.007 – 901.532)	0.264	-	-

Abbreviations: HR, hazard ratio; ECOG-PS, eastern cooperative oncology group performance status; IPI, international prognostic index; LDH, lactate dehydrogenase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; SVC, superior vena cava

Table 3. Logistic regression analysis of factors associated with EOT PET-CT results

Variables	Overall survival
	Univariate		Multivariate
	HR (95%CI)	*P-value*	HR (95%CI)	*P-value*
Age > 40 years	0.927 (0.216 – 3.986)	0.919	-	-
Male	1.588 (0.473 – 5.330)	0.454	-	-
ECOG-PS ≥ 2	2.533 (0.598 – 10.738)	0.207	-	-
Stage ≥ III	0.750 (0.223 – 2.521)	0.642	-	-
IPI ≥ 3	1.300 (0.223 – 7.578)	0.771	-	-
Bulky (≥10 cm) disease	4.000 (0.849 – 18.836)	0.080	2.018 (0.273 – 14.949)	0.492
LDH elevated	0.579 (0.124 – 2.700)	0.487	-	-
Extra-nodal involvement	1.481 (0.412 – 5.322)	0547	-	-
Pleural involvement	1.667 (0.271 – 10.244)	0.581	-	-
Pericardial involvement	1.300 (0.223 – 7.578)	0.771	-	-
SVC syndrome present	1.300 (0.223 – 7.578)	0.771	-	-
Positive interim PET-CT	31.714 (5.788 – 173.779)	<0.001	28.755 (5.166 – 160.038)	<0.001

Abbreviations: EOT, end-of-treatment; HR, hazard ratio; ECOG-PS, eastern cooperative oncology group performance status; IPI, international prognostic index; LDH, lactate dehydrogenase; SVC, superior vena cava

Table 4. Summary of studies on rituximab-containing treatment in primary mediastinal large B-cell lymphoma

Reference (year)	Study size	Study type	Front-line regimen	Consolidation	Median age, years	PFS/EFS (median)	OS (median)	Prognostic factors
HK Ahn (2010)	35	Retrospective	R-CHOP (60%) CHOP (40%)	RT (57.1%)	30 (range, 17-79)	2yr PFS 79.0% vs 50.0%	2yr OS 82.7% vs 57.1%	Achievement of CR (OS, PFS)
Rieger (2011)	87	Prospective	R+CHOP-like (50.6%) CHOP-like (49.4%)	RT (70.1%)	36 ( range, 27-43)	3yr EFS 78% vs 52%	3yr OS 89% vs 78%	Rituximab-containing regimen (EFS) age-adjusted IPI (EFS) bulky disease (OS, EFS)
Vassilakopoulos (2012)	76	Retrospective	R-CHOP (100%)	RT (68.4%)	31.5 ( range, 17-73)	5yr EFS 80%	5yr OS 89%	None
Xu (2013)	79	Retrospective	R-CHOP (49.4%) CHOP-like (50.6%)	RT (75.9%)	29 ( range, 13-54)	5yr PFS 76.7% vs 44.2%	5yr OS 83.7% vs 48.3%	Rituximab-containing regimen (OS, PFS) RT (PFS) LDH (OS, PFS) stage III/IV (OS, PFS)
Dunleavy (2013)	51	Phase 2	DA-EPOCH-R (100%)	None	30 ( range, 19-52)	5yr PFS 93%	5yr OS 97%	N/A
Aoki (2014)	345	Retrospective	R-CHOP (54.2%) DA-EPOCH-R (2.6%) CHOP (12.7%)	RT (42%) ASCT (16.5%)	32 ( range, 17-83)	4yr PFS 75% vs 54%	4yr OS 91% vs 77%	Pleural or pericardial effusion (PFS) stage III/IV (PFS)
Soumerai (2014)	63	Retrospective	R-CHOP (100%)	RT (77%)	37 ( range, 20-82)	5yr PFS 68^	5yr OS 79%	Advanced stage (PFS) age>60 years (OS, PFS) multiple extra-nodal site (OS, PFS)
HJ Ahn (2014)	25	Retrospective	R-CHOP (64.0%) CHOP (28.0%) Others (8.0%)	RT (36%) ASCT (16%)	31 ( range, 15-85)	3yr PFS 71.4% vs 68.2%	3yr OS 85.7% vs 62.5%	Poor performance status (OS) B symptoms (OS) SVC syndrome (OS)
Gleeson (2016)	50	Phase 3 Subgroup analysis	R-CHOP (100%)	RT (58%)	38.5 (range, 22-78)	5yr PFS 79.8%	5yr OS 83.8%	N/A
Lisenko (2017)	80	Retrospective	R-CHO(E)P (56%) CHO(E)P (44%)	RT (88%) ASCT (30%)	37 (range, 18-64)	10yr PFS 95% vs 67%	10yr OS 92% vs 72%	Rituximab-containing regimen (OS, PFS) Achievement of CR (OS, PFS)
Giulino-Roth (2017)	118	Retrospective	DA-EPOCH-R (100%)	RT (16.1%)	34 (range, 21-70)	3yr EFS 87.4%	3yr OS 97.1%	Negative end-of-therapy PET (EFS)
Shah (2018)	132	Retrospective	R-CHOP (54.2%) DA-EPOCH-R (2.6%)	RT (32.6%)	35 (range, 18-77)	2yr PFS 76% vs 85%	2yr OS 89% vs 91%	N/A
Melani (2018)	93	Retrospective	DA-EPOCH-R (100%)	None	31 (range, 18-68)	8yr EFS 90.6%	8yr OS 94.7%	N/A
Messmer (2019)	43	Retrospective	R-CHOP (76.7%) DA-EPOCH-R (21%)	RT (23%)	36 (range, 16-60)	3yr PFS 93% vs N/A	3yr OS 100% vs N/A	N/A
Chan (2019)	124	Retrospective	R-CHOP (62.9%) DA-EPOCH-R (37.1%)	RT (29.8%)	27 (range, 11-72)	5yr PFS 56.5% vs 90%	5yr OS 76.1% vs 96.9%	B symptoms (OS) Primary treatment regimen (PFS)
Malenda (2020)	53	Retrospective	R-CHOP (47.6%) DA-EPOCH-R (52.4%)	RT (49.1%) ASCT (18.9%)	30 (range, 18-80)	1yr PFS 87% vs 73.9%	1yr OS 100% vs 92%	ASCT (OS)
Zhou (2020)	166	Retrospective	R-CHO(E)P (86.7%) R-HyperCVAD (11.4%) others (1.8%)	RT (51.2%) ASCT (15.1%)	33 (range, 11-64)	5yr PFS 70%	5yr OS 79%	Ki-67 ≥70% (OS, PFS) MUM1 status (OS) CBC lymphocyte/monocyte ratio (PFS)
Hayden (2020)	159	Retrospective	R-CHOP (94%) R-containing (6%)	RT (44%)	36 (range, 19-84)	5yr PFS 79%	5yr OS 89%	Stage III/IV (PFS) Pleuralpericardial effusion (PFS)
Stepanishyna (2020)	69	Prospective (Abstract)	R-CHOP (47.8%) DA-EPOCH-R (52.2%)	RT (N/A)	27 (range, 17-45)	5yr PFS 64.1% vs 90.9%	5yr OS 73.8% vs 97.7%	N/A
Wästerlid (2021)	172	Prospective	R-CHO(E)P (73.8%) DA-EPOCH-R (7%) R-containing (11%)	RT (17%)	37.5 (range, 18-85)	5yr relative survival 88%		Increasing age (relative survival) Performance status (relative survival) age-adjusted IPI (relative survival)
Held (2023)	131	Phase 3 subgroup analysis	R-CHOP (100%)	RT (62.6%)	34 (range, 18-60)	3yr PFS 93%	3yr OS 97%	LDH (OS, PFS) stage III/IV (OS, PFS)
Zucca (2023)	545	Phase 3 (Abstract)	R-containing (100%)	RT (25%)	N/A	30 month PFS 98.5% vs 96.2%	5yr OS 99% vs 99%	N/A
This study (2024)	65	Retrospective	R-CHOP (90%) DA-EPOCH-R (10%)	RT (44.6%)	32 (16-86)	3yr PFS 72%	3yr OS 81%	Consolidative RT (PFS) End-of-therapy PET (PFS)

Abbreviations: PFS, progression-free survival; EFS, event-free survival; OS, overall survival; RT, radiation therapy; ASCT, autologous stem cell transplant; R, rituximab; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; DA-EPOCH, dose-adjusted ddd; CHOEP, aaa; CR, complete response; IPI, international prognostic index; LDH, lactate dehydrogenase; PET, positron emission tomography; N/A, not available; SVC, superior vena cava;

Table 5. Summary of studies on use of immune checkpoint inhibitors to treat relapsed or refractory primary mediastinal large B-cell lymphoma

Study	Patients	Study type	Front-line regimen	Prior transplantation	Prior lines of treatment (median)	ICI	ORR	CR	Number of treatment (median)	Survival outcomes
KEYNOTE-013	21	Phase 1b	R+CTx (100%)	42.9%	3 (range, 2-9)	Pembrolizumab	48%	33%	N/A	1yr PFS 47% 1yr OS 65%
KEYNOTE-170	53	Phase 2	R+ CTx (100%)	26.4%	3 (range, 2-8)	Pembrolizumab	41.5%	20.8%	N/A	Median PFS 4.3 mon. Median OS 22.3 mon.
CheckMate 436	30	Phase 1/2	R+CTx (100%)	13.3%	2 (range, 2-5)	Nivolumab	73.3%	40.0%	5 (range, 1-35)	2yr PFS 55.5% 2yr OS 75.5%
SJ Kim et al.	4	Retrospective	N/A	50%	4 (range, 3-6)	Pembrolizumab	50%	0%	2.5 (range, 1-12)	N/A
Y Qin et al.	4	Retrospective	N/A	N/A	N/A	Toripalimab Pembrolizumab Nivolumab Sintilimab	100%	100%	N/A	Median PFS: Patient 1: 21.2 mon. Patient 2: 21.6 mon. Patient 3: 22.9 mon. Patient 4: 29.2 mon.
B Casadei et al.	27	Retrospective	MACOP-B±R	N/A	3 (range, 2-8)	Pembrolizumab Nivolumab	N/A	37%	N/A	N/A
This study	12	Retrospective	R+CTx (100%)	8.3%	3 (range, 1-6)	Pembrolizumab Nivolumab	58.3%	25%	3 (range, 1-24)	1 yr PFS 20% 1 yr OS 54%

Abbreviations: ICI, immune checkpoint inhibitor; ORR, objective response rate; CR, complete remission; R, rituximab; CTx, chemotherapy; N/A, not available; PFS, progression-free survival; OS, overall survival; MACOP-B, methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin

No competing interests reported.

Real-world data analysis of survival outcomes of patients with primary mediastinal large B- cell lymphoma treated with upfront consolidative radiation therapy following immunochemotherapy

Status:

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Abstract

Background

Methods

Results

Conclusions

Figures

Background

Methods

Study overview

Primary treatment

Subsequent treatment

Statistical analysis

Results

Patient characteristics

Primary treatment for ND-PMBCL

Survival outcomes according to response evaluation with PET-CT

RR-PMBCL after primary treatment failure

Discussion

Abbreviations

Declarations

Competing interests

Author Contribution

Acknowledgements

Availability of data and materials

References

Tables

Additional Declarations

Status:

Version 1