
==== Front
J Cancer Res Clin Oncol
J Cancer Res Clin Oncol
Journal of Cancer Research and Clinical Oncology
0171-5216
1432-1335
Springer Berlin Heidelberg Berlin/Heidelberg

39299973
5956
10.1007/s00432-024-05956-3
Research
Sintilimab plus GemOx is an effective salvage therapy in patients with refractory/relapsing nodal peripheral T cell lymphomas
Xiao Xibin 1
Hu Mengmeng 2
Jiang Huawei 1
Chen Panpan 1
Lei Huyi 450506193@qq.com

2
1 grid.268505.c 0000 0000 8744 8924 Department of Hematology, The Second Affiliated Hospital, College of Medicine, ZhejiangUniversity, Hangzhou, China
2 https://ror.org/0435tej63 grid.412551.6 0000 0000 9055 7865 Department of Hematology, Affiliated Hospital of Shaoxing University(Shaoxing Municipal Hospital), Shaoxing, Zhejiang People’s Republic of China
19 9 2024
19 9 2024
2024
150 9 4256 8 2024
13 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Purpose

The retrospective study was to explore the effectiveness and safety of GemOx (gemcitabine, oxaliplatin) plus sintilimab (belongs to the class of drugs known as immune checkpoint inhibitors, particularly targeting the PD-1 receptor) in relapse or refractory nodal PTCLs.

Methods

Patients with nodal PTCL who initiated salvage therapy with sintilimab and GemOx between January 2020 to September 2021 were identified from the database of the hematology department of the Second Affiliated Hospital of Zhejiang University School of Medicine. All patients received 2–4 cycles (3 weeks/cycle) of treatment of sintilimab (200 mg, I.V, D1) in combination with GemOx. Treatment response was assessed every six weeks during the salvage treatment phase. Eligible patients received maintenance therapy according to the investigator’s decision. Follow-ups were routinely conducted every three months.

Results

31 patients with r/r nodal PTCLs were enrolled, including 23 PTCL-NOS, 4 AITL, and 4 ALCL. 21 (67.7%) patients received at least two lines of therapy. 71.0% (95% CI, 53.4%-83.9%) of patients documented objective response of 2–4 cycles of sintilimab plus GemOx therapy, including 9 complete response and 13 partial response. 21 (67.7%) patients received consolidation therapy, including 5 autologous stem-cell transplantation and 12 histone deacetylase inhibitors. After a median 25.6 months follow-up, the median PFS was 22.0 (95% CI,11.8–24.7) months, and the median OS was 26.2 (95% CI, 24.4 –NA) months. 29 (93.5%) patients experienced at least one adverse event, and 26 (83.9% patients only had mild (grade 1–2) AEs.Univariable Cox regression showed the progression risk of AITL is 22.7 (3.9- 131.0, p < 0.01) times of PTCL-NOS, while the HR of ALCL was 1.14 (0.33–3.96,p = 0.833).

Conclusion

Sintilimab plus GemOx showed encouraging activity and manageable toxicity for patients with r/r PTCL.

Keywords

PTCL
GemOx
Sintilimab
Salvage therapy
Chemoimmunotherapy
issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2024
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pmcIntroduction

Peripheral T cell lymphomas (PTCLs), derived from mature post-thymic lymphocytes, are a heterogeneous group of rare malignancies. PTCLs account for around 25% of non-Hodgkin lymphoma (NHL) patients in China and about 10% in the USA and Europe (Sun et al. 2012; Vose et al. 2008). PTCLs were classified into four groups in the 2017 World Health Organization (WHO) classification: nodal, extranodal, leukemic, and primary cutaneous. The main nodal PTCLs include PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL) (Swerdlow et al. 2016).

The rarity and heterogeneity of PTCLs limit the study of new treatments in clinical trials. Thus, chemotherapy remains the mainstay of treatment for PTCL.

Anthracycline-containing chemotherapy such as CHOP (cyclophosphamide + vincristine + doxorubicin + prednisone) and CHOP-like regimens are commonly used first-line for all PTCL subtypes except extranodal NK-/T-cell lymphoma (ENKTL). However, the effectiveness is unsatisfactory, with a low response rate. Once relapse or progression, treatment options are minimal. GemOx (gemcitabine, oxaliplatin) is one of the regimens recommended in NCCN guidelines for refractory⁄relapsing (r/r) PTCL. However, the median overall survival (OS) is only 6.5 months (Ellin et al. 2014).

Recently, many studies demonstrated that many PTCLs constitutively express Programmed Death-1(PD- 1) or Programmed Death-Ligand 1

(PD-L1) (Miyoshi et al. 2016; Shen et al. 2019), which revealed the potential of immune checkpoint inhibitors (ICIs) in managing PTCLs. ICIs have achieved promising results in treating ENKTL subtypes (Tao et al. 2021). However, the efficacy needs to be improved in other subtypes of PTCL. In a phase II single-arm study, pembrolizumab only showed moderate activity in relapsed or refractory T-cell lymphoma (Barta et al. 2019).Fortunately, many trials have demonstrated the synergistic effect of chemotherapy and immunotherapy in solid tumors (Lu et al. 2022; Yang et al. 2021). Previous reports on sintilimab in T cell lymphoma have demonstrated its potential efficacy in this disease setting (Tao et al. 2021).We would like to know whether PD- 1 inhibitors combined with chemotherapy could be an effective salvage regimen in PTCLs. Thus, we designed a retrospective study to explore the effectiveness and safety of GemOx plus sintilimab-a selective anti-PD- 1 antibody-in relapse or refractory nodal PTCLs.

Methods

Study design and patients

Patients with nodal PTCL who initiated salvage therapy with sintilimab and GemOx between January 2020 to September 2021 were identified from the database of the hematology department of the Second Affiliated Hospital of Zhejiang University School of Medicine. The inclusion criteria were ( 1) adult patients (Age≥18) with histologically confirmed nodal PTCL, including PTCL-NOS; AITL; ALCL, Anaplastic Lymphoma Kinase( ALK)-positive; ALCL, ALK-negative; (2) had failed at least one prior systemic therapy; (3) at least one measurable lesion as defined by Lugano criteria (Cheson et al. 2014); (4) received at least one response assessment (CT or PET-CT). Patients were excluded if prior exposure to any anti-PD- 1/PD-L1 or anti-cytolytic T lymphocyte-associated antigen-4 (CTLA-4) antibody; prior exposure to gemcitabine and oxaliplatin.

The study protocol was approved by the institutional ethics review board and was conducted according to the Declaration of Helsinki. The ethics review board waived informed consent due to the retrospective, non-interventional nature of the study.

Treatment and follow-up

All patients received 2-4 cycles (3 weeks/cycle) of treatment of sintilimab (200mg, I.V, D1) in combination with GemOx (gemcitabine 800-1200mg/m2, oxaliplatin 135mg/m2), treatment response was assessed every six weeks during the salvage treatment phase. Eligible patients received maintenance therapy according to the investigator’s decision.Maintenance therapy is a long-term treatment strategy aimed at controlling disease progression, prolonging patient survival, and improving their quality of life through continuous medication or other treatment modalities.In our study, maintenance therapy was a personalized treatment plan formulated by physicians based on the specific condition and physical status of the patient. Follow-ups were routinely conducted every three months.

Outcomes

The primary endpoint was ORR, defined as the proportion of patients with the best overall response, including complete response (CR) and partial response (PR), per the Lugano criteria. The secondary outcomes included progression-free survival (PFS), OS, and safety. PFS was calculated from the date salvage therapy was initiated until disease progression (clinical or radiologic) or death from any cause, whichever occurred first. OS was calculated from the date salvage treatment was initiated until death from any cause. Efficacy outcomes were also analyzed in subgroups of patients by PD-L1 expression and pathological subtype. Safety was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.

Statistical analysis

Continuous variables are presented as mean and standard deviation (SD) if normally distributed or median and interquartile range (IQR). Categorical variables are presented as percentages. Exact binomial confidence intervals (CIs) were calculated for ORR. PFS and OS were analyzed using the Kaplan-Meier method, and data were censored at the last visit in the absence of a progression event or death. All analyses were performed using R-3.4.1.

Results

Patients and treatment

Of 35 adults identified who initiated sintilimab and GemOx salvage therapy for nodal PTCL between January 2020 to September 2021, 31 were included in the analysis (Fig. 1).Fig. 1 Study Profile

Patient demographics, diseases, and prior treatment characteristics are shown in Table 1.Table 1 Baseline characteristics

Characteristic	N = 31	
Gender		
 Female	10 (32%)	
 Male	21 (68%)	
Age (IQR)

ECOG PS

	56 (36, 68)	
 0	2 (6.5%)	
 1	26 (84%)	
 2	1 (3.2%)	
 3	2 (6.5%)	
Pathological subtype		
 ALCL ALK-	1 (3.2%)	
 ALCL ALK + 	3 (9.7%)	
 AITL	4 (13%)	
 PTCL−NOS	23 (74%)	
Stage of disease		
 I	3 (9.7%)	
 II	10 (32%)	
 III	6 (19%)	
 IV	12 (39%)	
PD-L1 expression		
 Positive	13 (42%)	
 Negative	18 (58%)	
 Prior HDAC inhibitors	14 (45%)	
 Prior chemotherapy	30 (97%)	
Prior lines of systemic therapy		
 1	10 (32%)	
 2	13 (42%)	
 3	8 (26%)	
IQR: interquartile range, ECOG PS: Eastern Cooperative Oncology Group Performance Status, ALK: anaplastic lymphoma kinase

Patients were a median age of 56 years (range 18-78), and most (67%) were male. The pathological subtype was PTCL-NOS in 23 patients (74.2%), AITL, and ALCL, each in four patients ( 12.9%). Previous one-line therapy had been received by ten patients (32.3%) and at least two by 21 patients (67.7%). Almost all patients (30, 96.8%) had received chemotherapy, and nearly half (45.2%) received HDAC inhibitors. Seven patients received two cycles of sintilimab and GemOx therapy, while 24 received four.

Efficacy

Treatment responses to sintilimab and GemOx included CR in nine patients, PR in 13 patients, SD in three patients, and PD in six patients. The ORR was 71.0% (95% CI, 53.4%-83.9%), and the Disease Control Rate(DCR) was 80.6% (95% CI, 63.7%-90.8%). 21 (67.7%) patients received consolidation therapy, five received autologous stem-cell transplantation (auto-SCT), 12 received histone deacetylase (HDAC) inhibitors, three were sintilimab, and one was brentuximab vedotin.

On February 1st, 2023, 23 patients recorded disease progression, and 17 died; eight were still under treatment. The median follow-up time was 25.6 months. Median PFS was 22.0 (95% CI, 11.8–24.7) months, one-year PFS rate was 64.5% (95% CI, 49.7–83.8 %) (Figure 2A). Fig. 2 A Kaplam-Meier estimated progression-free survival of entire cohort. B Kaplam-Meier estimated progression-free survival by PD-L1 expression. C Kaplam-Meier estimated progression-free survival by pathological subtype

Median OS was 26.2 (95% CI, 24.4 – NA) months, the one-year and two-year OS rate was 77.4% (95% CI,64.0–93.6%) and 67.2% (95% CI, 52.4–86.2%), respectively (Fig. 3A). Fig. 3 A Kaplam-Meier estimated progression-free survival of entire cohort. B Kaplam-Meier estimated progression-free survival by PD-L1 expression. C Kaplam-Meier estimated progression-free survival by pathological subtype

In the subgroup analysis that included PD-L1 positive patients (n = 13), the ORR was 69.2% (95% CI, 42.4–87.3%), median PFS was 19.5 (95% CI, 3.2-NA) months(Fig. 2B) and median OS was 26.2 (95% CI, 16.9-NA) months (Fig. 3B). In PD-L1 negative patients, the ORR was 72.2% (95% CI, 49.1–87.5%), the median PFS was 22.2 (95% CI, 13.8-NA) months, and the median OS was 25.9 (95% CI, 23.5-NA) months. The ORR,median PFS, and median OS were 82.6% (95% CI, 62.9–93.0%), 22.8 (95% CI, 20.4-NA) months, and 26.3 (95% CI, 25.2-NA) months in PTCL-NOS group. The ORR, median PFS, and median OS were 75.0% (95% CI, 30.1–95.4%), 22.1 (95% CI, 3.7-NA) months, 25.6 (95% CI, 3.8-NA) months in ALCL group. The efficacy in AITL was the worst with 0% ORR, and all of them progressed in three months; the median PFS was 2.1 (95% CI, 0.9-NA) months (Fig. 2C) and OS was 5.8 (95% CI, 2.2-NA) months (Fig. 3C).Univariable Cox regression showed that PD-L1 expression status was not a prognostic factor, while pathological subtype significantly correlated with prognosis. The PFS hazard ratio (HR) of PD-L1 positive was 1.28 (0.56–2.94, p = 0.556), and the OS HR was 1.10 (0.42–2.88, p = 0.839). The progression risk of AITL is 22.7 (3.9- 131.0, p < 0.01) times of PTCL-NOS, while the HR of ALCL was 1.14 (0.33–3.96, p = 0.833). The death risk of AITL was the highest, with 12.20 (2.84–52.48, p = 0.001) times of PTCL-NOS, while ALCL was 1.85 (0.38–8.95, p = 0.442).

Safety

29 (93.5%) patients experienced at least one adverse event (AE) (Table 2), and 26 (83.9% patients only had mild (grade 1–2) AEs.Table 2 Treatment-related toxicities during sintilimab plus GEMOX therapy

Adverse events	Any grade	Grade 1–2	Grade 3	
Neutropenia	27 (87.1)	26 (83.9)	1 (3.2)	
Anemia	21 (67.7)	21 (67.7)	0	
Nausea	21 (67.7)	21 (67.7)	0	
Thrombocytopenia	14 (45.2)	13 (41.9)	1 (3.2)	
Anorexia	14 (45.2)	14 (45.2)	0	
Elevated ALT	14 (45.2)	14 (45.2)	0	
Oral mucositis	12 (38.7)	12 (38.7)	0	
Abnormal thyroid function	11 (35.5)	11 (35.5)	0	
Fatigue	11 (35.5)	11 (35.5)	0	
Elevated total bilirubin	10 (32.3)	10 (32.3)	0	
Diarrhea	8 (25.8)	7 (22.6)	1 (3.2)	
Vomit	8 (25.8)	8 (25.8)	0	
Elevated direct bilirubin	7 (22.6)	7 (22.6)	0	
Decreased fibrinogen	7 (22.6)	7 (22.6)	0	
Mouth pain	6 (19.4)	6 (19.4)	0	
Shingles	5 (16.7)	5 (16.7)	0	
Elevated lipase	5 (16.1)	5 (16.1)	0	
Rash	4 (12.9)	4 (12.9)	0	
Decreased albumin	4 (12.9)	4 (12.9)	0	
Bleeding	4 (12.9)	4 (12.9)	0	
Elevated triglycerides	3 (9.7)	3 (9.7)	0	
Hypertension	3 (9.7)	3 (9.7)	0	
Infusion fever	3 (9.7)	3 (9.7)	0	
Thrombotic event	2 (6. 5)	2 (6.5)	0	
Proteinuria	1 (3.2)	1 (3.2)	0	

The most common AEs were chemotherapy-related, including neutropenia (n = 27, 87.1%), anemia (n = 21,67.7%), nausea (n = 21, 67.7%), anorexia (n = 14, 45.2%), elevated ALT (n = 14, 45.2%) and thrombocytopenia (n = 14, 45.2%). The most common immune-related AEs (irAEs) were abnormal thyroid function (n = 11, 35.5%). Three patients experienced grade 3 AE; one was neutropenia, one was thrombocytopenia, and the other was diarrhea. No patient reported grade 4–5 AEs.

Discussion

This is the first published study to evaluate the efficacy and safety of an immune.

checkpoint inhibitor in combination with GemOx in patients with nodal PTCL. Our result reflects a substantial activity of this regimen, with a 71% response rate and 67.7%patients successfully bridging to consolidation therapy, yielding a 26-month median OS. Autologous stem cell transplantation remains the first choice for r/r PTCL(Sibon 2022). Studies reported that the 3- to 5-year OS is approximately 50% after autoSCT in CR/PR adults(Garcia-Sancho et al. 2022; Smith et al. 2013). Therefore, partial remission should be achieved as soon as possible to create autologous stem cell transplantation conditions.GEMOX-R showed substantial activity with a 43% response rate and 34% complete remissions. The response rate of sintilimab plus GemOx is higher,whereas complete remissions are comparable. Of note, Ló pez, A. et al. recruited elderly patients, and we enrolled heavily treated patients. The high response rate of sintilimab plus GemOx provided an opportunity for autoSCT, and five patients received autoSCT successfully, which contributed partially to the prolonged median OS. Consolidation therapy typically refers to additional treatment administered after the primary treatment (such as chemotherapy or radiotherapy) to further eliminate residual cancer cells or prevent disease recurrence. In our study, of the patients unfit or refused autoSCT, HDAC inhibitor consolidation is a major treatment pattern. Shi Y et al. conducted a phase II study to evaluate the efficacy of chidamide, an HDAC inhibitor, in r/r PTCL in the Chinese population and reported 21.4 months median overall survival (Shi et al. 2015). Our study results are in accordance with their findings. HDAC inhibitor consolidation might provide a new option for unfit patients.

AITL is a unique entity of PTCL with distinct pathologic features and poor prognosis (Fiore et al. 2020). Some results of clinical studies indicated the concern of using PD- 1 antibodies in T cell lymphoma patients, which might accelerate tumor progression. A previous study of nivolumab in patients with r/r PTCL recruited six AITL patients and reported hyper-progressive disease in four patients (Bennani et al. 2019). Four AITL patients were enrolled in our study, and all progressed in three months, in line with previous findings. By contrast, Shi Y et al. enrolled four AITL and reported two PR and two SD in a phase II study evaluating an ICI in r/r PTCL (Shi et al. 2021). However, the application of siltilmab in the studies reviewed has been accompanied by a notable array of side effects, underscoring the need for careful consideration and monitoring in its clinical use.Numerous side effects have also been observed during the application of siltilmab in the aforementioned studies.It should pay more cautious about applying ICIs to these patients.Most adverse events in this regimen were around grades 1 to 2. Common hematologic toxicities included agranulocytosis and thrombocytopenia, and can be resolved with supportive therapy. Non-hematological toxicities, including autoimmune-mediated hypothyroid ism, rash, and diarrhea, are the primary concerns. Overall, the safety was manageable, and no patient discontinued treatment due to severe complications.

Limitations of this study included the absence of a control arm and single institute experience. In addition, the sample size is relatively small, partially due to the rarity of this entity. Therefore, a randomized control trial with a larger sample size is warranted to further investigate this regimen in this population.

Conclusions

In conclusion, sintilimab plus GemOx showed encouraging activity and manageable toxicity for patients with r/r PTCL. Further investigations in randomized controlled trials are warranted.

Acknowledgements

Authors also appreciate the contributions from all the investigators, the patients and their families.

Author contributions

Xibin Xiao: conception, design,manuscript writing and final approval of manuscript. Mengmeng Hu: data analysis and interpretation, and manuscript writing.Huawei Jiang, Panpan Chen: collection and assembly of data and project administration.Huyi Lei:provided financial support for the research, offered guidance and assistance in the design and implementation of the study, and offered valuable feedback and suggestions for the preparation and revision of the manuscript.

Funding

No.2022KY415.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. No datasets were generated or analysed during the current study.

Declarations

Conflicts of interest

The authors declare no conflict of interest.

Ethical approval

Our study complies with the Declaration of Helsinki and was approved by the hospital ethics committee. (IR2022495).

Informed consent statement

Patient consent was waived due to the retrospective, non-interventional nature..

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Xibin Xiao and Mengmeng Hu contributed equally to this work.
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