Background
Worldwide, aggressive B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma (NHL) [
1,
2]. The standard first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy achieves long-term remission in approximately two-thirds of adult patients and others suffer from primary refractory or relapsed (R/R) lymphoma after an initial response [
1,
3]. Although many efforts have been made to improve patient survival over the past two decades, including increase dose-send/intensity of systemic therapy, maintenance therapy, and R-CHOP plus a novel drug (R-CHOP + X), the standard of care for unspecified patients has not changed [
4,
5]. Hence, many new therapeutic approaches have been developed that focus on R/R diseases [
6‐
10].
The standard of care for patients with late relapse (> 12 months) is high-dose chemoimmunotherapy with autologous stem-cell transplantation (ASCT) if the disease is responsive to salvage regimens [
1,
5,
7,
11,
12]. However, because of aging, concurrent morbidities, and chemoresistance, only 25% patients are considered candidates for transplantation [
7,
13‐
16]. Autologous chimeric antigen receptor (CAR) T-cell therapy, a gene-modified cellular treatment, represents a major paradigm shift in the management of R/R B-cell lymphomas [
6,
17,
18]. To avoid a delay in constitutes infusion, several retrospective trials have used radiotherapy (RT) as a bridging or salvage strategy for CAR T-cell therapy, with reported response rates of 80–88% [
19‐
26].
The efficacy of RT to improve local control of aggressive B-cell lymphoma is well established [
27‐
34]. In addition, several large database analyses have shown improved survival with the addition of RT after controlling for confounding factors through multivariate analysis in the rituximab era [
35‐
38]. Recently, in a comprehensive retrospective study (British Columbia Cancer Lymphoid Cancer Database), the positron emission tomography (PET)-positive sites of some patients who received RT for nonprogressive disease showed results comparable to those with PET-negative findings [
39]. Additionally, the predominant pattern of relapse following systemic therapy (including first-line chemotherapy, ASCT, and CART) often involve sites of initial [
21,
40‐
43]. These predictable patterns of relapse emphasize the utility of RT to improve local control to all sites of disease. However, an interval of over 4 weeks induced by RT, which can delay systemic salvage therapies for R/R patients, is a crucial concern for hematologists.
Regardless of a consolidation or salvage setting, conventional RT has been shown to be a safe and promising tool to help control the disease; however, the clinical value of hypofractionated RT is still poorly understood. The aim of this study was to investigate the outcomes and toxicity of hypofractionated RT in R/R patients in a single facility.
Methods
Eligibility and study population
Patients with R/R aggressive B-cell lymphoma between January 2020 and August 2022 at a single institution were retrospectively reviewed (n = 59). The eligibility criteria included R/R patients who had received hypofractionated RT prior to or after salvage systemic treatment. Patients who had received conventional fractionated RT (n = 17), showed central nervous system (CNS) involvement, or had primary CNS lymphoma (n = 12) were excluded. Eventually, 30 patients were eligible for the final analysis.
Evaluation and definition
Patients were initially staged according to the Ann–Arbor staging system and scored using the international prognostic index. The tumor response was evaluated after completion of chemotherapy, RT, or a combination of chemotherapy and RT. Complete response (CR) was defined as the elimination of all signs of disease in the clinical and imaging examinations. Refractory disease was defined as an incomplete response after primary chemotherapy. Relapsed disease was defined as new disease found on imaging or biopsy after CR. All patients were re-evaluated with CT scan before RT, and 26 patients (86.7%) also underwent a PET scan. Adverse events were evaluated using CTCAE (common terminology criteria for adverse events) version 5.0.
In- and out-of-field relapses for RT were defined based on imaging or biopsy. If the failure occurred in the same area of the lymph node that had been irradiated, it was deemed to be an in-field relapse. If the failure occurred in an area of the distant lymph node other than outside the irradiated area, it was considered an out-of-field relapse. Out-of-field relapse after RT was categorized as pre-existing sites only, new sites only, or both. Relapse at pre-existing sites was defined as a recurrent disease at the same sites before first-line chemotherapy. Relapse at new sites was identified as a recurring disease outside of sites prior to first-line treatment.
Treatment
Immunochemotherapy was considered the primary treatment of aggressive B-cell lymphoma. All patients were treated with immunochemotherapy and the regimens were R-CHOP (n = 26) and dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab, n = 4). The median number of chemotherapy cycles was 4 (range: 3–8).
Radiotherapy was given with a 6-MV linear accelerator. As directed by the International Lymphoma Radiation Oncology Group (ILROG), involved-site radiation therapy (ISRT) was administered [
44,
45]. PET or magnetic resonance imaging (MRI) were obtained and co-registered with planning CT to improve delimitation of the treatment volume. Gross tumor volume (GTV) was defined as residual diseases in PET/CT or CT. Adjacent nodal diseases that responded to chemotherapy may be included in the clinical target volume (CTV), as long as their inclusion was not associated with significant toxicity. A 3–7-mm margin was added to the GTV and CTV to generate the corresponding planning gross target volume (PGTV) and planning target volume (PTV), respectively. The median dose for GTV was 36 Gy (range: 30–39 Gy), at a dose per fraction of 2.3–5 Gy. Since December 2021, 24 Gy to PTV with a simultaneous integrated boost 36 Gy to PGTV in 12 fractions were widely applied at our institution (
n = 23, 76.7%). The numbers of treated sites was defined as the numbers of radiation field required to treat all target volumes. Organs at risk (OAR) included the parotid glands, larynx, spinal cord, lungs, heart, kidney, liver, small intestine, bladder, rectum, and head of the femur.
Statistical analysis
Continuous variables were reported in medians and ranges, and categorical variables were reported in frequencies and percentages. The primary endpoint was response to RT, defined as either CR or partial response (PR); secondary endpoints included progression-free survival (PFS) and overall survival (OS). PFS was defined as the period from the date of RT to the date of any relapse, progression, last follow-up, or death from any cause. OS was calculated from the date of RT to the date of death from any cause or until the last follow-up. PFS and OS were estimated using the Kaplan–Meier method and compared using log-rank tests stratified by prognostic factors. P < 0.05 was considered to indicate statistically significant differences. All statistical analyses were performed using SPSS (version 26.0; IBM Corporation, Armonk, NY, USA) and R (version 3.5.3) software.
Discussion
Although the standard treatment for R/R aggressive B-cell lymphoma with late relapse (> 12 months) is dose-intensity chemotherapy followed by ASCT, most older patients are not considered ideal transplant candidates. The addition of consolidation or salvage RT unequivocally reduces the risk of local failure; however, a critical concern has been how to deliver RT in a short period of time, which did not delay effective systemic therapy. To our knowledge, this is the first study to provide valuable data of comprehensive hypofractionated RT for R/R aggressive B-cell lymphoma. Hypofractionated short-course RT exhibits excellent local control with mild toxicities.
The treatment options for R/R aggressive B-cell lymphoma show physician discrepancy and geographic variations between different countries or institutions, including chemotherapy alone, CAR T-cell therapy, and a sequential combination of chemotherapy and RT with or without ASCT [
46‐
51]. Owing to heterogeneous treatments, a small number of patients receiving RT with different doses and fractions [
28,
45,
52‐
54]. Recent studies have demonstrated that short-course bridging RT prior to CAR T-cell therapy provides excellent local control and a sustainable response. Theoretically, patients who will never be suitable for CAR T-cell therapy because of medical insurance-related issues and physical performance that may benefit from comprehensive hypofractionated RT [
19‐
24,
55]. In this study, we present a homogenous cohort of 30 patients suffering from R/R aggressive B lymphoma. The comprehensive hypofractionated RT had an excellent response, with ORR and CR rates of 90% and 80%, respectively.
Salvage RT as part of potential treatment strategy is generally considered after second- or third-line systemic therapy. According to the ILROG guidelines for nodal NHL, patients with R/R disease unsuitable for transplantation may benefit from RT with doses up to 55 Gy [
54]. Consequently, subsequent systemic treatment may be delayed for up to 6 weeks. The 2020 ILROG emergency RT guideline recommend hypofractionated schemes (36–39 Gy in 12–13 fractions or 30 Gy in six fractions) for chemorefractory NHL [
44]. Recently, a cross-sectional study conducted by Memorial Sloan Kettering Cancer Center identified that the increased usage of hypofractionated RT was unique to sites affiliated with the hospital [
54]. In our institution, the majority of lymphoma patients received IMRT or VMAT, and all R/R aggressive B-cell lymphoma received hypofractionated schemes since 2021 (36 Gy in 12 fractions). The median RT fraction was 12 in this study, fewer than the recent large retrospective study from British Columbia Cancer Agency (30–40 Gy in 15–20 fractions) [
39].
As a non-cross-resistant therapy, RT could be a bridge to ASCT or CAR T-cell therapy to deepen remissions and improve cure rates. Metabolic tumor volume (MTV), as a representative of the total burden of disease, is the most important predictor of outcome in DLBCL and other lymphoma subtypes, regardless of the measurement method and study time points [
56‐
59]. Here, we also showed that patients achieving CR after RT showed higher survival rates than those without CR. However, this high ORR rate was not entirely translated into an OS benefit. Out-of-field relapses continue to be a challenge, particularly in patients with advanced-stage disease, non-response to initial chemotherapy, or with multiple residual lesions at the time of RT. Similarly, 80% relapsed diseases occurred in new sites in our study. Therefore, the new agent should be added to RT to enhance the effects without obvious toxicity. At present, there are a number of clinical trials establishing the effects of immune checkpoint inhibitors in Hodgkin’s lymphoma [
60‐
62]. However, DLBCL patients had a low response rate to the immune checkpoint inhibitor because chromosome 9p24.1 genetic alterations and PD-L1 or PD-L2 expression are rare in DLBCL. Hypofractionated RT can enhance the release of tumor antigens, increase tumor-reactive T cells, and work synergistically with immune checkpoint inhibitors in many solid tumors [
63]. Presently, the combination of pembrolizumab and hypofractionated RT (20 Gy in five fractions) is in the phase 2 trial with R/R NHL (NCT04827862). To validate the above assumptions, we also performed a multicenter, single-arm, phase 2 study (ChiCTR2200060059) to assess the potential impact of Zimberelimab plus hypofractionated RT in patients with primary refractory DLBCL. The study is currently enrolling patients. The clinical benefit of hypofractionation RT and immune checkpoint inhibitors needs to be further investigated in these prospective studies.
This study has some limitations, mainly related to its retrospective nature. While the data support important findings regarding a high response rate and mild toxicities with hypofractionated RT, the treatments were not randomly assigned. Additionally, none of the patients received CAR T-cell therapy. Although CAR T-cell therapy has been recommended based on the guidelines, is not cost effective and may not be feasible for most patients in China. In fact, the data we observed that could provide an option for CAR T-cell therapy-eligible patients. Furthermore, because of the short follow-up period, we were unable to adequately assess the late toxicities. However, hypofractionated RT has been widely employed in several types of solid tumors with long-term follow-up. We believe that hypofractionated RT is efficacious and safe.
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