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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 2  |  Page : 525-531

The efficacy of PD-1 inhibitors in the maintenance treatment of diffuse large B-cell lymphoma: A single-center retrospective analysis


Department of Hematology and Oncology, National Cancer Center/ National Clinical Research Cancer for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China Institute of Infection, Immunology and Tumor Microenviroment, Medical College, Wuhan University of Science and Technology, Wuhan, China

Date of Submission29-Jan-2022
Date of Decision12-Mar-2022
Date of Acceptance18-Mar-2022
Date of Web Publication20-May-2022

Correspondence Address:
Qiang Wang
Institute of Infection, Immunology and Tumor Microenviroment, Medical College, Wuhan University of Science and Technology, Wuhan
China
Zhi Guo
Department of Hematology and Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_255_22

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 > Abstract 


Purpose: To explore the impact of PD-1 maintenance therapy on the relapse-free survival (RFS) of patients with diffuse large B-cell lymphoma (DLBCL).
Methods: We retrospectively analyzed patients with DLBCL admitted to our center between January 2018 and July 2019 who achieved complete remission (CR) after induction chemotherapy. Forty-five patients who received PD-1 inhibitor maintenance therapy were considered the treatment group. Forty-five patients who did not undergo maintenance treatment during the same period were selected as the control group. The base levels of the two groups of patients were similar. The 2-year RFS rate of the two groups was compared. The correlation between the adverse prognosis factors of the patients and the RFS rate was performed subgroup analysis.
Results: The 2-year RFS rates of the treatment and control groups were 86.7% VS 75.6% (P = 0.178), respectively, until July 2021. A single factor analysis showed that patients with International Prognostic Index (IPI) score ≥ 3, non-GCB DLBCL receiving PD-1 inhibitor maintenance treatment, can improve their 2-year RFS (72.2% VS 30.8%, P = 0.022; 88.5% VS 62.5%, P = 0.032). For non-GCB patients, the 2-year RFS of the treatment group can reach 88.5%, while the 2-year RFS of the control group is 62.5%, which is statistically significant (P = 0.032). In all patients treated with PD-1 inhibitors, the adverse reactions were all grade I–II, and there were no grade III–IV adverse reactions. There were no clear adverse events in the follow-up patients in the control group.
Conclusion: Maintenance treatment with PD-1 inhibitors can improve the 2-year RFS rate of patients with IPI score of ≥3 and non-GCB DLBCL. This prompts the potential advantage of PD-1 inhibitors in DLBCL maintenance treatment. However, longer follow-ups remain needed to obtain more definite data.

Keywords: Diffuse large B-cell lymphoma, maintenance therapy, PD-1 inhibitors, prognostic factors, relapse-free survival


How to cite this article:
Wei Ly, Xie J, Wang Yq, Liu Xy, Chen X, Zhang Yh, Wang Q, Guo Z. The efficacy of PD-1 inhibitors in the maintenance treatment of diffuse large B-cell lymphoma: A single-center retrospective analysis. J Can Res Ther 2022;18:525-31

How to cite this URL:
Wei Ly, Xie J, Wang Yq, Liu Xy, Chen X, Zhang Yh, Wang Q, Guo Z. The efficacy of PD-1 inhibitors in the maintenance treatment of diffuse large B-cell lymphoma: A single-center retrospective analysis. J Can Res Ther [serial online] 2022 [cited 2022 Oct 1];18:525-31. Available from: https://www.cancerjournal.net/text.asp?2022/18/2/525/345541

Li-ya Wei, Jing Xie, Yue-qiao Wang contributed equally to this work





 > Introduction Top


Diffuse large B-cell lymphoma (DLBCL) is the most common subtype in non-Hodgkin's lymphoma. The overall survival (OS) could reach 60% after five years with routine chemotherapy.[1] The prognosis is extremely poor once refractory or relapse occurs.[2],[3] Rescue treatments, including hematopoietic stem cell transplantation and new small-molecule targeted drugs combined with chemotherapy, are difficult to achieve significant results. Most patients achieved complete remission (CR) after sufficient courses of chemotherapy in the induction chemotherapy phase.[4] However, some residual tumor remains in the body. DLBCL is an aggressive lymphoma with significant heterogeneity. In the rituximab era, the ability to identify risk stratification is limited. For poor prognostic factors, such as high International Prognostic Index (IPI) score, MYC immunohistochemistry or gene rearrangement are more likely to relapse.[5],[6],[7],[8] By increasing the chemotherapy cycle, the chemotherapy effect reached the upper limit and adverse reactions were more obvious.[9],[10] Choosing a noncytotoxic drug regimen with a new antitumor mechanism as a sequential maintenance treatment to reduce the recurrence rate is a new direction for aggressive lymphoma with high recurrence risk.[11] There are few positive results in DLBCL maintenance treatment in previous clinical studies. Rituximab as a maintenance treatment for DLBCL failed in the study. Maintenance treatment with bortezomib and ibrutinib in DLBCL had little effect on the OS.[12] Recently, applying the programmed death receptor inhibitors-1 (PD-1) in malignant tumors has been attracting increasing attention.[13] It has been proven effective in Hodgkin's lymphoma, extranodal NK/T cell lymphoma, and primary mediastinal large B-cell lymphoma.[14],[15],[16] PD-1 has been included in various guidelines and recommendations, but its clinical application in DLBCL remains in the exploratory stage.[17],[18] This study retrospectively analyzed the effect of maintenance therapy with PD-1 inhibitors in our center on DLBCL.


 > Methods Top


Study design and patients

A retrospective analysis of patients with DLBCL who were admitted to the Department of Hematology and Oncology in Cancer Hospital, Chinese Academy of Medical Sciences, Shenzhen center and who achieved complete remission after induction chemotherapy between January 2018 and July 2019 was done. Forty-five patients who received PD-1 inhibitor maintenance therapy were set as the treatment group. Forty-five patients who did not undergo maintenance treatment during the same period were selected as the control group. All patients diagnosed with DLBCL by pathological biopsy after obtaining CR chose to observe or receive PD-1 inhibitor maintenance treatment. Clinical data included imaging data (enhanced computed tomography (CT) or positron emission tomography-computed tomography (PET-CT)), cell origin, bone marrow invasion, presence or absence of large masses (defined as lesion length >7.5 cm), B symptoms (fever, night sweats, and weight loss), the IPI, and so on. We collected the general clinical data of the treatment and control groups. The data in the patient's baseline blood biochemical examination included gender, age, physical status score, and Eastern Cooperative Oncology Group (ECOG) score. For patients in the maintenance treatment group, complete brain natriuretic peptide, thyroid function, fasting blood glucose, blood lipids, and cortisol were needed.

Treatment

All patients in the treatment group received PD-1 inhibitor treatment for more than six cycles (maximum two years) until the patient developed intolerable toxicity or the disease progressed. Nivolumab 3-mg/kg was intravenously injected once every 2–3 weeks, each lasting 60 minutes. Pembrolizumab 2-mg/kg intravenous infusion for 30 minutes was done; above all, it was administered once every 3–4 weeks. Sintilizumab 200 mg intravenous infusion for more than 60 minutes was done once every 3–4 weeks; teriprizumab 3 mg/kg intravenous infusion was done once every 2–3 weeks. Adverse reactions, such as skin rash, hypothyroidism, and leukopenia during treatment would be given corresponding symptomatic and supportive treatment. The control group was observed and did not receive any drug treatment. The corresponding salvage treatment would be selected according to the patient's condition if the disease recurred.

Assessments

The efficacy evaluation was judged according to the efficacy evaluation criteria established by the World Health Organisation (WHO), which are divided into CR, partial remission (PR), stable disease, and progressive disease (PD). Relapse-free Survival (RFS) is defined as the time from disease remission to initial relapse. The imaging evaluation of the two groups of patients was performed according to the enhanced CT or PET-CT review every 3–6 months for the first 1–2 years, and the enhanced CT or PET-CT every 12 months for the 3–5 years of re-examination and evaluation. Supposing the two groups of patients had disease recurrence and progression during maintenance treatment or follow up, then they would be adjusted to the posterior antitumor treatment plan following the relevant lymphoma guidelines or consensus. During PD-1 inhibitor treatment, attention must be paid to monitoring blood routine, liver and kidney function, fasting blood glucose, blood lipids, BNP, cortisol, thyroid function, and other hematological tests. The deadline for follow up of all patients was 31 July 2021.

Statistical analysis

SPSS version 22.0 was used for statistical analysis. Quantitative data conforming to the normal distribution were expressed as x ± s, and it did not obey the normal distribution and was expressed as the median (range). The t test or Z-test compared the two groups of two independent samples. The number of cases and percentages expressed qualitative data, and comparisons between groups were performed using χ2 test or Fisher's exact probability method. The gender, IPI score, cell origin, age, ECOG score, B symptoms, bone marrow invasion, and large masses were included in the univariate analysis. Univariate analysis used Kaplan–Meier survival analysis, and longrank analysis was used to test survival outcome indicators. The test level was 0.05.


 > Results Top


Patient baseline characteristics

A total of 90 patients with DLBCL with CR after treatment (45 per group) were included in this retrospective analysis. There were 25 males and 20 females in the treatment group with a median age of 49.7 years (21–78 years), and 13 cases were above 60 years old. There were 23 males and 22 females in the control group with a median age of 48.8 years (26–76 years), and 13 cases were above 60 years old. The treatment and control groups had symptoms of B (7/45 vs 8/45, P = 0.777), Ki-67 ≥70% (32/45 vs 33/45, P = 0.814), and IPI score ≥3 points (18/45 vs 13/45, P = 0.267), large mass (11/45 vs 9/45, P = 0.612), ECOG score ≥ 2 points (6/45 vs 5/45, P = 0.748), cell origin (non-germinal center B-cell-like (NON-GCB) 26/45 vs 24/45, P = 0.671), bone marrow invasion (8/45 vs 9/45, P = 0.788), and other factors. The difference was not statistically different. There were no special abnormalities in the baseline level of blood routine, biochemical results, thyroid function, cortisol level, blood glucose and lipid metabolism level, BNP, etc. [Table 1].
Table 1: Patient baseline characteristics

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Treatment

Patients in the treatment group received single-agent PD-1 inhibitors (5 pembrolizumab cases, 6 nivolumab cases, 16 sintilizumab cases, and 18 teriprizumab cases). The median duration of treatment for patients was 13.2 (6–24) months. Six patients (6/45, 13.3%) progressed and changed other treatment options to continue treatment, and three patients died from disease progression (3/45, 6.7%). None of the patients in the treatment group discontinued the drug due to treatment toxicity and other factors. In the control group, eleven patients (11/45, 24.4%) progressed and received other treatment options to continue treatment, and seven patients (7/45, 15.6%) due to disease progression.

Efficacy

The deadline for follow-up was 31 July 2021. The median follow-up time of the control group was 31.5 (15–42) months, and the median follow-up time of the treatment group was 30.2 (12–42) months. The control group showed a certain survival improvement trend in OS [see [Figure 1]] and RFS compared to the treatment groups [Figure 2], but it did not reach statistical significance. The 2-year RFS rates of the treatment and control groups were 86.7% vs 75.6% (P = 0.178). A single factor analysis showed that patients with IPI scores ≥3 receiving PD-1 inhibitor maintenance treatment could improve their 2-year RFS (72.2% vs 30.8%, P = 0.022); there was a significant statistical difference [Figure 3]. For non-GCB patients, the 2-year RFS of the treatment group could reach 88.5%, while the 2-year RFS of the control group was 62.5%, which was statistically significant (P = 0.032) [Figure 4]. However, age, gender, ECOG score, B symptoms, bone marrow invasion, and other factors had no effect on whether patients receiving PD-1 maintenance treatment could prolong RFS [Table 2].
Figure 1: Kaplan–Meier survival curve of patients in treatment group and control group

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Figure 2: Kaplan–Meier relapse-free survival rate curve of treatment group and control group

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Figure 3: Kaplan–Meier relapse-free curve in the treatment group and the control group in patients with IPI ≥3

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Figure 4: Kaplan–Meier relapse-free curve of non-GCB patients in the treatment group and the control group

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Table 2: Two-year RFS subgroup analysis

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Safety

In all patients treated with PD-1 inhibitors, the adverse reactions were all grades I–II, and there were no grades III–IV adverse reactions. The main adverse reactions were six cases of I–II degree leukopenia (6/45, 13.3%), five cases of grade I–II rash (5/45, 11.1%), three cases of I–II degree hypothyroidism (3/45, 6.7%), two cases of I–II degree liver damage (2/45, 4.4%). There were no adverse reactions such as immune pneumonia, cardiac insufficiency, and abnormal cortisol. There were no clear adverse events in the follow-up patients in the control group. Compared with the control group, the treatment group had a higher incidence of skin rash, liver damage, decreased blood picture, hypothyroidism, and abnormal glucose and lipid metabolism. But they were all grade I–II and easily controlled.


 > Discussion Top


DLBCL has high heterogeneity in clinical features, histopathology, genetic features, etc. The first-line R-CHOP regimen had significantly improved the prognosis of patients, but patients still faced the progress of disease recurrence after induction chemotherapy having achieved CR. Previous studies showed that[19] most recurrence events after induction chemotherapy in patients with DLBCL remission occurred in the first two years, and the subsequent recurrence rate of patients after two years of event-free survival would be significantly reduced. The cumulative recurrence rate for the following three years was 6.9%, for five years was 9.3%, and eight years was 10.3%. This indicated that reducing the recurrence rate in the first two years after remission is particularly important. Maintenance treatment aims to select an effective and low-toxic therapeutic drug for a certain period of treatment to further eliminate the remaining small tumor cells in the patient, delay the patient's recurrence time as much as possible, and further prolong the patient's OS. Therefore, choosing an appropriate maintenance treatment plan is a new field of exploration, and it has also attracted significant attention from clinicians.[20],[21],[22]

PD-1 inhibitors are negative regulators of the immune system that protect tissues from immune collateral damage. These immune checkpoints are often enhanced by cancers that allow them to avoid the antitumor immune system.[23] The main mechanism of PD-1 inhibitors is to relieve the immune escape of tumor cells from T lymphocytes by binding to the PD-L1 receptor, then restore the killing effect of T cells in the human body on tumors, and finally achieve inhibiting tumor progression. Lymphoma has more clinical applications.[15],[24] Compared with traditional chemotherapeutics, immunotherapy has a fundamental difference in antitumor mechanism, and it has the advantages of the low incidence of adverse reactions and good tolerance. The latest clinical studies have shown that[25] the objective response rate (ORR) of pembrolizumab combined with R-CHOP in newly-treated DLBCL can be increased to 90% and the CR can reach 77%, without significantly increasing the adverse effects of treatment. However, more studies have shown that the efficacy of immune checkpoint inhibitors on DLBCL is uneven,[26] and that the single-agent PD-1 (nivolumab) has a poor response to the treatment of refractory and relapsed DLBCL.[27] ORR was 3%–10%. The median PFS was 1.4–1.9 months, the 6-month PFS rate was only 5.2%–19.1%, and the 6-month OS rate was 47%–67%. The inconsistent research results are mainly due to the high heterogeneity of DLBCL.[28],[29] Additionally, for DLBCL, the immune microenvironment of lymphoma is more complicated. The immune killing mechanism of DLBCL and finding reliable immunotherapy biomarkers may be a way out for immunotherapy of DLBCL in the future.[30],[31] Therefore, selecting DLBCL patients who are potentially effective for immunotherapy based on the characteristics of the patient's disease and receiving PD-1 inhibitor maintenance therapy may improve the RFS of these patients.

The current study selected the commonly used clinical PD-1 inhibitors as the maintenance treatment for patients with DLBCL after CR. By evaluating the maintenance treatment efficacy of 45 patients, the treatment group showed a certain improvement trend in RFS and OS compared with the control group. Factor analysis showed that the treatment group of patients with IPI score ≥3 and non-GCB DLBCL had a significant benefit compared with the control group in the 2-year RFS rate (72.2% vs 30.8%, P = 0.022; 88.5% vs 62.5%, P = 0.032). The ECOG4494 clinical trial[11] aimed to evaluate the efficacy of the rituximab maintenance group compared with the control group after receiving CHOP or R-CHOP induction therapy in patients with DLBCL who were ≥60 years old. The study results showed that rituximab maintenance treatment only improved the 2-year event-free survival of patients with PR or CR using CHOP induction chemotherapy. However, it did not improve the event-free survival of patients using R-CHOP induction therapy. In the REMARC study,[13] maintenance therapy with lenalidomide could improve the PFS of patients aged 60–80 years. The median PFS of the two groups was 54 months vs 38.6 months (P = 0.01), but the median follow-up was 52 months. There was no difference in OS between the lenalidomide and placebo groups over the past months. Compared with previous research, the results of this study showed that PD-1 inhibitors had certain advantages in controlling the recurrence of DLBCL, which was worthy of further exploration by clinicians. Of course, many factors affect the prognosis and treatment response of patients with DLBCL.[19] Precise patient selection meets the requirements of current precision treatment, which is also the key point affecting the success of maintenance treatment in DLBCL. What did the analysis suggest about the patients? The result of subgroup suggested that patients with IPI score ≥ 3 and non-GCB type the treatment group had a more obvious improvement in RFS than the control group. The possible reason is that most patients with high IPI scores have tumor stages. The tumor burden is relatively large. Even after conventional induction chemotherapy, it is difficult for patients with minimal residual lymphoma to turn negative. In non-GCB DLBCL, there is a higher proportion of PD-L1 on the surface of tumor cells. The expression status[32] is an independent poor prognostic factor in patients with DLBCL.[33] Patients with these two adverse prognostic factors are clinically more likely to have refractory relapses, and some have the most potential benefits for maintenance therapy. However, this study could not explain why maintenance therapy has not seen significant therapeutic benefits in the subgroups of other adverse factors. Further studies may be needed in the future on the independent influence of each adverse factor on the prognosis of patients with DLBCL and its potential mechanism of action, in order to explore a precise treatment plan for each adverse factor.

In addition to the efficacy, the safety of immunotherapy is also a major issue. Previous studies have shown[34] that the main adverse reactions caused by PD-1 inhibitor treatment include abnormal thyroid function, skin rash, immune pneumonia, blood sugar, abnormal blood lipid metabolism, decreased blood picture, cardiac insufficiency, abnormal cortisol secretion, and so on. This retrospective study showed that the treatment group injected with PD-1 inhibitors were safe and controllable. There were no discontinuations or deaths due to adverse reactions, indicating PD-1 inhibitor monotherapy is quite safe as a maintenance treatment of DLBCL. The safety data of this study was inconsistent with previous research data on immunotherapy on other solid tumors. The overall incidence of adverse reactions is low, and the severity is relatively small except for consideration and sample in addition to the small amount. To study whether immunotherapy has different immune-related adverse reaction mechanisms in lymphoma, especially DLBCL, remains unclear. It must be emphasized that the correlation of PD-L1 expression in the efficacy analysis of patients with DLBCL receiving immunotherapy is unclear. Firstly, the current immunohistochemical detection of PD-L1 lacks a unified interpretation standard, and the immunology of the pathology department of our center PD-L1 testing has not been routinely conducted in the group chemical project. Secondly, the drugs used in the treatment group included nivolizumab, pembrolizumab, sintilizumab, and teriprizumab. Although they belong to PD-1 inhibitors, their efficacy and safety remain different. Due to the small sample size, this study could not be further used for subgroup analysis and multivariate analysis of the treatment group, which may also have a certain impact on the study results. Finally, this was a single-center retrospective study. There was a certain selection bias in the enrolled patient population, mainly manifested in the willingness to receive maintenance treatment and the duration of maintenance treatment. Many factors greatly affected them, and this triggered the selection of the enrolled populations. In the future, prospective, multicenter, randomized controlled, and double-blind cohort studies are still needed to further confirm and explore the efficacy and safety of this program.

Acknowledgements

We thank Xiaohua Tan for critical reading and English editing of the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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