Prognostic Impact of Blood Transfusions During Nivolumab Therapy in Metastatic Non-Small Cell Lung Cancer

Abstract

Introduction

Immune checkpoint inhibitors (ICIs) are standard therapy for metastatic non-small cell lung cancer (NSCLC). Blood transfusions, particularly erythrocyte suspension (ES) transfusions, may induce immunomodulatory effects and potentially influence cancer outcomes. This study investigated the association between transfusions and survival in NSCLC patients treated with nivolumab.

Methods

We retrospectively reviewed 88 patients with metastatic NSCLC who received nivolumab between January 2018 and December 2023. Transfusion status, baseline inflammatory markers, progression-free survival (PFS), and overall survival (OS) were evaluated. Survival outcomes were assessed using Kaplan–Meier analysis and univariable statistical methods.

Results

The median patient age was 64 years (range, 41–76). Median PFS was 5.93 months (95% Confidence Interval [CI], 3.72–8.14), and median OS was 8.23 months (95% CI, 6.19–10.27). Patients who received ES transfusions during nivolumab therapy experienced shorter PFS (p=0.033) and OS (p=0.039), predominantly driven by the non-squamous subgroup (PFS: p=0.002; OS: p=0.008). In univariable analyses, nivolumab cycle count, pre-treatment hemoglobin, neutrophil-to-lymphocyte ratio (NLR), C-reactive protein-to-albumin ratio (CAR), and systemic immune-inflammation index were associated with PFS, while programmed cell death ligand-1 (PD-L1) status, treatment line, number of cycles, pre-treatment hemoglobin, NLR, CAR, and prognostic nutritional index were associated with OS (all p< 0.05).

Conclusion

ES transfusions administered during nivolumab therapy were associated with poorer PFS and OS in patients with metastatic NSCLC, particularly in those with non-squamous histology. Given the retrospective design and limited number of transfused patients, these findings should be interpreted with caution and considered hypothesis-generating. Larger, prospective multicenter studies are warranted to further clarify the relationship between transfusion exposure and ICI outcomes.

Keywords

immune checkpoint inhibitors immunotherapy erythrocyte suspension blood transfusion non-small cell lung cancer nivolumab survival

Introduction

Lung cancer remains the leading cause of cancer-related mortality worldwide and is the second most commonly diagnosed malignancy in both sexes.¹ Non-small cell lung cancer (NSCLC) accounts for approximately 87% of all lung cancer cases, and 30–40% of patients present with metastatic disease at diagnosis.^1,2 Given its high prevalence and mortality, the management of NSCLC represents a major focus in contemporary oncology practice.

In recent years, immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of NSCLC, offering improved response rates and survival outcomes compared with conventional chemotherapy (CT).³ ICIs are now established as standard therapy across both metastatic and non-metastatic settings—including neoadjuvant, adjuvant, perioperative, and maintenance treatment following chemoradiotherapy (CRT)—either as monotherapy or in combination with CT.^4-10 These agents enhance antitumor immunity by blocking inhibitory receptors such as cytotoxic T-lymphocyte antigen-4, programmed cell death-1 (PD-1), and lymphocyte activation gene-3 on T lymphocytes.^11,12 Because ICIs rely on immune activation for their efficacy, conditions that impair immune function, particularly T-cell activity, may diminish their therapeutic effect.

Anemia is the most common hematologic abnormality in cancer patients and may even represent the initial manifestation of malignancy.¹³ It is typically multifactorial, resulting from disease-related factors, treatment toxicity, or patient comorbidities.¹⁴ Management of anemia is an integral component of oncologic care, and erythrocyte suspension (ES) transfusion is frequently administered for treatment-related anemia, perioperative support, or symptomatic relief.¹⁵ However, blood transfusion has been associated with immunomodulatory effects that may adversely impact cancer outcomes—a phenomenon referred to as transfusion-related immunomodulation (TRIM).¹⁶ In lung cancer, perioperative blood transfusion has been correlated with poorer survival in multiple studies, including a meta-analysis of 18 trials encompassing 5915 patients.¹⁷ In another meta-analysis evaluating survival outcomes from 18 studies involving patients with esophageal cancer who underwent esophagectomy, perioperative ES transfusion was associated with poorer survival compared to patients who did not receive transfusion. The same analysis also demonstrated that patients who received three or more units of ES had worse survival outcomes than those who received two units or fewer.¹⁸

The proposed mechanisms underlying this immunosuppressive effect include reduced immune surveillance due to the infusion of viable leukocytes, apoptotic cells, and biologically active mediators contained in blood products.^15,19 Such mechanisms raise concern for a potential negative interaction between blood transfusions and ICIs, given their dependence on immune activation.

Other blood components, including thrombocyte suspension (TS), fresh frozen plasma (FFP), and cryoprecipitate, are also commonly used in oncology patients with coagulopathies.²⁰ Platelets can promote tumor growth and metastasis by releasing metabolites (e.g., thromboxane, serotonin), growth factors such as vascular endothelial growth factor, and platelet-derived microparticles (PMPs), which have proangiogenic and proinflammatory properties that contribute to tumor progression.^21-24 Similarly, FFP has been suggested to directly stimulate cancer cell proliferation.¹⁵ Thus, non-ES blood products might also modulate immune activity in ways that could influence ICI outcomes.

To optimize the efficacy of ICIs, it is essential to identify and minimize factors that impair immune function. Prior studies have shown that concurrent use of immunosuppressive agents—such as corticosteroids or antibiotics—can reduce ICI efficacy.^25,26 Given the known immunomodulatory and potentially immunosuppressive effects of blood transfusions, limiting their use in patients treated with ICIs may warrant consideration, particularly when alternative strategies are available. Therefore, in this study, we aimed to evaluate the relationship between ES transfusion, with secondary consideration of other blood products (TS and/or FFP), and treatment efficacy and safety in patients with metastatic NSCLC receiving nivolumab (anti–PD-1). Based on this rationale, we hypothesized that transfusion exposure—and particularly the timing of transfusion (before, during, or after nivolumab)—may be associated with differences in survival outcomes in patients undergoing ICI therapy.

Methods

This retrospective, observational study included patients aged ≥18 years with metastatic (stage IV) NSCLC who received nivolumab at our tertiary medical oncology center between January 1, 2018, and December 31, 2023. Eligible patients were evaluated to determine whether they received ES, TS, and/or FFP before, during, or after nivolumab treatment, and to assess the associations between transfusion status, transfusion timing, and survival outcomes.

Patient information was obtained from hospital electronic records and physical files. Demographic and clinicopathological characteristics, disease stage at diagnosis, metastatic sites, prior systemic treatments, nivolumab treatment line, regimen, and number of cycles were recorded. Laboratory data, including hemoglobin, neutrophil, lymphocyte, platelet, albumin, and C-reactive protein levels prior to nivolumab initiation, were collected. Additionally, data regarding ABO and Rhesus factor (Rh) blood groups, transfusion status before, during, and after nivolumab, the types of transfused blood products (ES, TS, FFP), and total transfusion volume were reviewed. Although multiple blood products were recorded, all transfusion-related analyses predominantly reflect ES exposure. Baseline comorbidity burden was assessed using the Charlson Comorbidity Index (CCI), retrospectively calculated from medical records at the time of nivolumab initiation.

Transfusion timing was categorized into three predefined groups. Before nivolumab was defined as the period from the date of metastatic diagnosis—or the date of metastasis development in patients who were initially non-metastatic—until the administration of the first dose of nivolumab. During nivolumab corresponded to the interval between the first and the last nivolumab dose. After nivolumab was defined as the period from the final nivolumab dose to the date of last follow-up or death. This categorization was used to provide temporal context for transfusion exposure; however, no time-dependent modeling was performed.

Using hemogram and biochemical parameters, several previously validated indices with known prognostic significance in various malignancies were calculated, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), C-reactive protein-to-albumin ratio (CAR), hemoglobin-albumin-lymphocyte-platelet score (HALP), and prognostic nutritional index (PNI).^27-33 The reporting of this study conforms to the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) guidelines for the evaluation of prognostic biomarkers. In addition, the study design and reporting adhere to the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines for observational cohort studies.^34,35

Progression-free survival (PFS) was defined as the time from the initiation of nivolumab treatment to documented disease progression or death from any cause. Overall survival (OS) was defined as the time from the start of nivolumab treatment to death from any cause. Patients who had not experienced progression or death at the time of analysis were censored at the date of their last documented follow-up for both PFS and OS. Time to first ES transfusion was defined as the interval between the first nivolumab administration and the date of the first ES transfusion recorded during nivolumab therapy. Treatment response to nivolumab was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Adverse events (AEs) of any grade were recorded and graded based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Statistical Analysis

Statistical analyses were performed using IBM SPSS Statistics version 25.0. Categorical variables were presented as frequencies and percentages, while continuous variables were expressed as mean ± standard deviation, median, and range (minimum–maximum). The Kolmogorov–Smirnov and Shapiro–Wilk tests were applied to assess the normality of data distribution. For comparisons between two groups, the independent samples t-test was used for normally distributed continuous variables, and the Mann–Whitney U test was used for non-normally distributed variables. Categorical variables were compared using the Chi-square test. Survival analyses were conducted using the Kaplan–Meier method, and survival curves were compared using the Log Rank test. Univariable Cox proportional hazards regression analyses were conducted to evaluate potential predictive factors associated with PFS and OS. Due to the limited number of events within certain subgroups—particularly the small number of patients who received transfusions during nivolumab therapy—a reliable multivariable Cox regression model could not be performed. Receiver-operating characteristic (ROC) curve analysis was exploratorily employed to determine optimal cutoff values for continuous variables, which were separately applied to PFS and OS analyses. Missing data were handled using a complete-case approach. A p-value of less than 0.05 was considered statistically significant.

Ethical Approval and Informed Consent

The study involving human participants was approved by the ethics committee of our academic medical center. The study was conducted in accordance with all relevant institutional regulations and local legislation. Written informed consent was waived by the Ethics Committee because the study involved a retrospective analysis of fully anonymized patient data. All patient information was fully de-identified before analysis, and no identifiable personal data were collected or disclosed. All procedures adhered to the ethical standards of the institutional research committee and complied with the principles of the Declaration of Helsinki (1975), as revised in 2024.

Results

During the study period, a total of 103 patients received nivolumab for metastatic NSCLC. Of these, 15 patients were excluded due to incomplete clinical data, and the remaining 88 patients were included in the final analysis. The median age of the patients was 64 years (range, 41–76), and 73 patients (83.0%) were male. The median follow-up duration in the metastatic setting was 1.77 years (range, 0.20–7.44). Non-squamous histology was identified in 59 patients (67.0%), while 52 patients (59.1%) presented with metastatic disease at diagnosis. The most common metastatic site at diagnosis was the bone (25 patients, 48.1%). All patients received nivolumab treatment in the metastatic setting. Regarding treatment lines, 43 patients (48.9%) received nivolumab as second-line therapy, 17 (19.3%) as first-line, 16 (18.2%) as third-line, six (6.8%) as fourth-line, four (4.5%) as fifth-line, and two (2.3%) as seventh-line therapy. The median number of nivolumab cycles administered was 8 (range, 1–93).

During the metastatic stage, 32 patients (36.4%) received blood transfusions before nivolumab, 16 (18.2%) during nivolumab, and 9 (10.2%) after nivolumab treatment. The demographic and clinicopathological characteristics of all patients and subgroups, stratified according to transfusion status during nivolumab therapy, are summarized in Table 1.

Table 1.

Comparison of Clinical Features Between Transfused and Non-transfused Patients During Nivolumab Treatment

Characteristics	All patients	Blood transfusion during nivolumab treatment		p
Characteristics	(N = 88)	Yes (n = 16)	No (n = 72)
Age at Diagnosis	64 (41-76)	58 (48-75)	65 (41-76)	0.101
Non-Squamous Histology	59 (67.0%)	13 (14.8%)	46 (52.3%)	0.181
Male Sex	73 (83.0%)	12 (13.6%)	61 (69.3%)	0.461
Charlson Comorbidity Index	9 (6-12)	8 (6-11)	9 (7-12)	0.268
Presence of De Novo Metastasis	52 (59.1%)	9 (10.2%)	43 (48.9%)	0.798
Site of Metastasis at Diagnosis^a
Non-Regional Lymph Node	8 (15.4%)	2 (3.8%)	6 (11.5%)	0.615
Pleura	6 (11.5%)	1 (1.9%)	5 (9.6%)	1.000
Lung	12 (23.1%)	3 (5.8%)	9 (17.3%)	0.415
Bone	25 (48.1%)	6 (11.5%)	19 (36.5%)	0.284
Adrenal Gland	10 (19.2%)	0 (0.0%)	10 (19.2%)	0.178
Liver	8 (15.4%)	3 (5.8%)	5 (9.6%)	0.130
Brain	14 (26.9%)	1 (1.9%)	13 (25.0%)	0.415
Curative Surgery Status	20 (22.7%)	5 (5.7%)	15 (17.0%)	0.509
Curative CRT Status	19 (21.6%)	3 (3.4%)	16 (18.2%)	1.000
Palliative RT Status	70 (79.5%)	13 (14.8%)	57 (64.8%)	1.000
PD-L1 Positive^b	19 (43.2%)	3 (6.8%)	16 (36.4%)	1.000
Nivolumab Second-Line	43 (48.9%)	9 (10.2%)	34 (38.6%)	0.342
Number of Nivolumab Cycles	8 (1-93)	4 (1-39)	9 (1-93)	0.031
Blood Group^c
A	35 (62.5%)	12 (21.4%)	23 (41.1%)	0.222
B	4 (7.1%)	2 (3.6%)	2 (3.6%)
0	12 (21.4%)	1 (1.8%)	11 (19.6%)
AB	5 (8.9%)	1 (1.8%)	4 (7.1%)
Rh Positive^c	50 (89.3%)	15 (26.8%)	35 (62.5%)	0.662
Time from Nivolumab Initiation to First ES Transfusion (months)^d	-	0.73 (0.03-8.27)	-	-
Laboratory Parameters Before Nivolumab Treatment^e
HGB	11.00 ± 1.59	9.76 ± 1.63	11.31 ± 1.44	<0.001
NLR	4.62 ± 3.79	5.70 ± 3.64	4.35 ± 3.81	0.023
PLR	209.42 ± 124.31	254.21 ± 140.55	198.23 ± 118.48	0.067
SII	1333.63 ± 1321.09	1924.42 ± 1626.29	1185.93 ± 1203.33	0.015
CAR	14.09 ± 16.41	23.08 ± 23.27	11.85 ± 13.53	0.049
HALP	32.23 ± 39.47	18.28 ± 10.88	35.73 ± 43.17	0.010
PNI	39.26 ± 5.96	35.57 ± 6.50	40.18 ± 5.49	0.017

^a52 patients (59.1%) had metastatic disease at diagnosis.

^b44 patients (50.0%) had known PD-L1 status.

^c56 patients (63.6%) had known ABO and Rh blood group status.

^dTime to first ES transfusion was calculated only for patients who received ES transfusions during nivolumab therapy.

^e81 patients (92.0%) had known laboratory parameters and calculations before nivolumab treatment.

CAR, C-reactive protein to albumin ratio; CRT, chemoradiotherapy; ES, erythrocyte suspension; HALP, hemoglobin albumin lymphocyte platelet score; HGB, hemoglobin; NLR, neutrophil-to-lymphocyte ratio; PD-L1, programmed death ligand-1; PLR, platelet-to-lymphocyte ratio; PNI, prognostic nutritional index; RT, radiotherapy; SII, systemic immune-inflammation index.

The median PFS was 5.93 months (95% Confidence Interval [CI], 3.72–8.14), and the median OS was 8.23 months (95% CI, 6.19–10.27). Among patients with non-squamous NSCLC, the median PFS was 5.13 months (95% CI, 1.63–8.64) and the median OS was 8.10 months (95% CI, 5.88–10.32). For squamous NSCLC, the median PFS was 7.16 months (95% CI, 4.82–9.50) and the median OS was 11.66 months (95% CI, 0.94–22.38). Kaplan–Meier survival curves are presented in Figure 1.

Figure 1.

Kaplan–Meier curves for progression-free survival (PFS) and overall survival (OS) according to blood transfusion status and histological subtype during nivolumab treatment

Kaplan–Meier analysis revealed significantly shorter PFS and OS in patients who received ES transfusions during nivolumab treatment (PFS: Log Rank p=0.033; OS: Log Rank p=0.039). Upon stratification by histological subtype, this association persisted only in the non-squamous subgroup (PFS: p=0.002; OS: p=0.008), but not in the squamous subgroup (PFS: p=0.493; OS: p=0.819). Given the limited number of patients receiving transfusions during nivolumab therapy, these subgroup analyses should be considered exploratory.

Univariable Cox regression analysis identified several variables associated with survival outcomes. Factors significantly affecting PFS included nivolumab cycle count, pre-nivolumab hemoglobin level, NLR, CAR, and SII (p<0.001, p=0.001, p=0.016, p=0.032, p=0.001, respectively). For OS, significant factors included programmed cell death ligand-1 (PD-L1) status, treatment line, nivolumab cycle count, pre-nivolumab hemoglobin, NLR, CAR, and PNI (p=0.028, p=0.011, p<0.001, p=0.001, p=0.026, p=0.002, and p=0.046, respectively). Detailed results of univariable Cox regression and ROC-based cut-off analyses are presented in Table 2.

Table 2.

Univariable Cox Regression Analysis of Clinical and Laboratory Factors Associated With Progression-free Survival (PFS) and Overall Survival (OS)

Factors	Category	PFS		OS
Factors	Category	HR (95% CI)	p	HR (95% CI)	p
Age at Diagnosis		0.993 (0.962-1.026)	0.692	0.999 (0.965-1.034)	0.949
Histological Subtype		0.901 (0.551-1.472)	0.677	0.859 (0.520-1.418)	0.552
Gender		0.862 (0.463-1.602)	0.638	0.926 (0.496-1.726)	0.808
Charlson Comorbidity Index	Ref: 9 and above	0.920 (0.577-1.466)	0.725	0.874 (0.542-1.407)	0.578
Presence of De Novo Metastasis		1.206 (0.747-1.945)	0.444	1.558 (0.950-2.555)	0.079
Pleural Metastasis at Diagnosis		0.947 (0.397-2.262)	0.903	1.026 (0.430-2.449)	0.953
Lung Metastasis at Diagnosis		1.262 (0.622-2.561)	0.520	1.401 (0.686-2.860)	0.355
Bone Metastasis at Diagnosis		1.405 (0.781-2.530)	0.257	1.401 (0.772-2.540)	0.267
Adrenal Gland Metastasis at Diagnosis		0.867 (0.403-1.866)	0.715	0.785 (0.349-1.767)	0.558
Liver Metastasis at Diagnosis		1.349 (0.597-3.050)	0.472	1.218 (0.541-2.742)	0.634
Brain Metastasis at Diagnosis		0.636 (0.320-1.264)	0.197	0.634 (0.319-1.261)	0.194
Curative Surgery Status		0.998 (0.565-1.766)	0.996	0.830 (0.468-1.473)	0.525
Curative CRT Status		0.696 (0.387-1.250)	0.225	0.602 (0.322-1.125)	0.112
Palliative RT Status		0.705 (0.404-1.229)	0.217	0.649 (0.365-1.154)	0.141
PD-L1 Status		2.054 (0.987-4.278)	0.054	2.371 (1.099-5.114)	0.028
Nivolumab Treatment Line		1.155 (0.956-1.397)	0.136	1.280 (1.058-1.549)	0.011
Number of Nivolumab Cycles		0.841 (0.803-0.880)	0.000	0.851 (0.811-0.893)	0.000
ABO Blood Group	Ref: A Group		0.372		0.492
B Group		1.322 (0.462-3.787)	0.603	1.492 (0.521-4.276)	0.456
0 Group		1.794 (0.446-7.217)	0.411	1.901 (0.472-7.663)	0.366
AB Group		2.253 (0.722-7.026)	0.162	2.231 (0.716-6.955)	0.167
Rh Blood Group		0.857 (0.596-1.230)	0.402	0.814 (0.555-1.194)	0.292
HGB	Low vs High*	0.759 (0.643-0.895)	0.001	0.763 (0.649-0.897)	0.001
NLR	Low vs High*	1.885 (1.126-3.158)	0.016	1.794 (1.072-3.001)	0.026
PLR	Low vs High*	1.484 (0.904-2.436)	0.118	1.638 (0.990-2.709)	0.055
SII	Low vs High*	1.755 (1.048-2.937)	0.032	1.607 (0.969-2.665)	0.066
CAR	Low vs High*	2.409 (1.427-4.068)	0.001	2.293 (1.347-3.903)	0.002
HALP	Low vs High*	0.680 (0.415-1.113)	0.125	0.638 (0.385-1.059)	0.082
PNI	Low vs High*	0.661 (0.415-1.077)	0.096	0.602 (0.365-0.992)	0.046

Cut-off values were determined using ROC curve analysis and applied separately for PFS and OS, respectively, as follows: NLR: 3.17, PLR: 177.15, SII: 730.31, CAR: 5.57, HALP: 28.32, and PNI: 40.01 for PFS; and NLR: 3.32, PLR: 181.24, SII: 815.69, CAR: 5.67, HALP: 28.32, and PNI: 40.01 for OS.

CAR, C-reactive protein to albumin ratio; CRT, chemoradiotherapy; HALP, hemoglobin albumin lymphocyte platelet score; HGB, hemoglobin; NLR, neutrophil-to-lymphocyte ratio; PD-L1, programmed death ligand-1; PLR, platelet-to-lymphocyte ratio; PNI, prognostic nutritional index; RT, radiotherapy; SII, systemic immune-inflammation index.

When stratified by pathological subtype, baseline characteristics were generally comparable between the non-squamous and squamous groups. The only notable difference was the higher rate of curative CRT received during the non-metastatic period in the non-squamous group (Table 3).

Table 3.

Patient Demographics and Clinical Characteristics According to Histological Subtype (Non-squamous vs. Squamous NSCLC)

Characteristics	All patients (N = 88)	Non-squamous (n = 59)	Squamous (n = 29)	p
Age at Diagnosis	64 (41-76)	62 (41-76)	65 (51-75)	0.220
Male Sex	73 (83.0%)	48 (54.5%)	25 (28.4%)	0.765
Charlson Comorbidity Index	9 (6-12)	9 (6-12)	9 (7-11)	0.340
Presence of De Novo Metastasis	52 (59.1%)	37 (42.0%)	15 (17.0%)	0.324
Site of Metastasis at Diagnosis^a
Non-Regional Lymph Node	8 (15.4%)	5 (9.6%)	3 (5.8%)	0.676
Pleura	6 (11.5%)	4 (7.7%)	2 (3.8%)	1.000
Lung	12 (23.1%)	9 (17.3%)	3 (5.8%)	1.000
Bone	25 (48.1%)	19 (36.5%)	6 (11.5%)	0.458
Adrenal Gland	10 (19.2%)	9 (17.3%)	1 (1.9%)	0.247
Liver	8 (15.4%)	6 (11.5%)	2 (3.8%)	1.000
Brain	14 (26.9%)	12 (23.1%)	2 (3.8%)	0.300
Curative Surgery Status	20 (22.7%)	14 (15.9%)	6 (6.8%)	0.749
Curative CRT Status	19 (21.6%)	9 (10.2%)	10 (11.4%)	0.039
Palliative RT Status	70 (79.5%)	45 (51.1%)	25 (28.4%)	0.277
PD-L1 Positive^b	19 (43.2%)	11 (25.0%)	8 (18.2%)	0.490
Nivolumab Second-Line	43 (48.9%)	29 (33.0%)	14 (15.9%)	0.311
Number of Nivolumab Cycles	8 (1-93)	6 (1-93)	9 (1-50)	0.705
Blood Group^c
A	35 (62.5%)	25 (44.6%)	10 (17.9%)	0.460
B	4 (7.1%)	3 (5.4%)	1 (1.8%)
0	12 (21.4%)	7 (12.5%)	5 (8.9%)
AB	5 (8.9%)	3 (5.4%)	2 (3.6%)
Rh Positive^c	50 (89.3%)	33 (58.9%)	17 (30.4%)	0.652
Receipt Blood Transfusion During Nivolumab Treatment	16 (18.2%)	13 (14.8%)	3 (3.4%)	0.181
ES	14 (15.9%)	11 (12.5%)	3 (3.4%)
ES + TS	1 (1.1%)	1 (1.1%)	0 (0.0%)
ES + FFP	1 (1.1%)	1 (1.1%)	0 (0.0%)
Median Number of ES Units Transfused During Nivolumab Treatment	1 (1-15)	1 (1-12)	2 (1-15)	0.439
Receipt Blood Transfusion Before Nivolumab Treatment	32 (36.4%)	22 (25.0%)	10 (11.4%)	0.797
Receipt Blood Transfusion After Nivolumab Treatment	9 (10.2%)	6 (6.8%)	3 (3.4%)	1.000
Laboratory Parameters Before Nivolumab Treatment^d
HGB	11.00 ± 1.59	10.93 ± 1.73	11.17 ± 1.28	0.527
NLR	4.62 ± 3.79	4.83 ± 4.30	4.11 ± 2.28	0.678
PLR	209.42 ± 124.31	212.11 ± 138.96	204.20 ± 84.17	0.551
SII	1333.63 ± 1321.09	1430.68 ± 1512.10	1105.47 ± 718.11	0.935
CAR	14.09 ± 16.41	15.09 ± 17.81	11.91 ± 12.86	0.464
HALP	32.23 ± 39.47	34.41 ± 46.45	27.44 ± 15.39	0.938
PNI	39.26 ± 5.96	38.72 ± 5.59	40.45 ± 6.67	0.160

^a52 patients (59.1%) had metastatic disease at diagnosis.

^b44 patients (50.0%) had known PD-L1 status.

^c56 patients (63.6%) had known ABO and Rh blood group status.

^d81 patients (92.0%) had known laboratory parameters and calculations before nivolumab treatment.

CAR, C-reactive protein to albumin ratio; CRT, curative chemoradiotherapy; ES, erythrocyte suspension; FFP, fresh frozen plasma; HALP, hemoglobin albumin lymphocyte platelet score; HGB, hemoglobin; NLR, neutrophil-to-lymphocyte ratio; NSCLC, non-small cell lung cancer; PD-L1, programmed death ligand-1; PLR, platelet-to-lymphocyte ratio; PNI, prognostic nutritional index; RT, radiotherapy; SII, systemic immune-inflammation index; TS, thrombocyte suspension.

Blood transfusions administered before nivolumab therapy in the metastatic stage had no significant impact on PFS or OS (PFS: p=0.863; OS: p=0.687). This finding remained consistent when analyzed separately for non-squamous (PFS: p=0.681; OS: p=0.672) and squamous subgroups (PFS: p=0.719; OS: p=0.766). Similarly, blood transfusions administered after nivolumab therapy completion did not influence PFS or OS (PFS: p=0.435; OS: p=0.783) in either histological subgroup (non-squamous: PFS p=0.443, OS p=0.877; squamous: PFS p=0.820, OS p=0.827).

Regarding best response, three patients (3.4%) achieved CR, 13 (14.8%) achieved PR, 42 (47.7%) had SD, and 30 (34.1%) had PD. For objective response (OR) evaluation, two patients (2.3%) achieved CR, 9 (10.2%) PR, 5 (5.7%) SD, and 72 (81.8%) PD. The median duration of nivolumab therapy was 3.96 months (95% CI, 2.23–5.69), while the median duration of response was 5.50 months (95% CI, 3.03–7.97).

The median CCI was 9 (range, 6–12), with no significant difference between transfused and non-transfused patients (p=0.268). No significant difference in PFS or OS was observed between patients with CCI ≤8 and those with CCI ≥9 (Log Rank p=0.725 and p=0.578, respectively).

Among those not receiving nivolumab as first-line, 52 patients (59.1%) had received carboplatin–paclitaxel, 9 (10.2%) received gemcitabine-based, and 8 (9.1%) received pemetrexed-based regimens. Following nivolumab, 24 patients (27.3%) underwent subsequent systemic therapy, with pemetrexed-based treatment being the most common (10 patients, 11.4%).

All 16 patients who received transfusions during nivolumab therapy were administered ES; among these, one patient also received TS and one received FFP. The median number of transfused ES units was 1 (range, 1–15). No significant association was observed between the number of ES units transfused during nivolumab treatment and survival outcomes, including PFS (p=0.948) and OS (p=0.869). Among patients who received transfusions during nivolumab therapy, the median time from nivolumab initiation to the first ES transfusion was 0.73 months (range, 0.03–8.27). Accordingly, transfusion-related analyses in this cohort predominantly reflect ES exposure.

AEs of any grade occurred in 38 patients (43.2%). The most frequent AEs were lower respiratory tract infection (13 patients, 14.8%) and hypothyroidism (8 patients, 9.1%). Grade 1–2 AEs were observed in 28 patients (31.8%), and Grade 3–4 AEs in 17 patients (19.3%). Two patients (2.3%) experienced grade 5 immune-related pneumonitis, resulting in death.

Discussion

In this study evaluating the efficacy of nivolumab in patients with metastatic NSCLC, we observed that ES transfusions administered during nivolumab therapy were associated with worse PFS and OS. This association was predominantly evident in patients with non-squamous histology. In contrast, ES transfusions administered before or after nivolumab treatment were not associated with adverse survival outcomes. As detailed in the Methods and Results sections, the transfusion-related analyses in this study primarily reflect ES exposure rather than other blood product types.

TRIM has been shown to influence immune function through several mechanisms, which may be particularly relevant in patients receiving ICIs. Soluble mediators and hemolysis-related products such as cell-free hemoglobin and heme can promote inflammatory imbalance and suppress key immune cell functions.^36,37 Additionally, immunomodulatory factors transferred with erythrocyte units may alter monocyte, T-cell, and natural killer-cell activity, and have been associated with increased infection risk and poorer oncologic outcomes in prior studies.^38,39 Therefore, in our cohort, differences in transfusion timing and patient characteristics may partly contribute to observed variations in treatment response and survival during nivolumab therapy through TRIM-related pathways. In our subgroup analysis, the adverse association between ES transfusion and survival was more pronounced in the non-squamous subgroup, whereas no significant impact was observed in patients with squamous histology. This difference may reflect underlying biological heterogeneity between histologic subtypes, including variations in baseline tumor immunogenicity and microenvironmental immune composition.^40,41 It is also possible that the limited sample size in the squamous subgroup reduced the power to detect a statistically significant effect. These findings should be considered hypothesis-generating and warrant validation in larger, prospective cohorts.

Our findings are consistent with those of Mispelbaum et al, who reported that ES transfusion within the first 60 days of initiating ICI therapy (atezolizumab, pembrolizumab, nivolumab, and/or ipilimumab) negatively affected treatment response in patients with solid tumors, whereas ES transfusion prior to immunotherapy had no such effect.⁴² Similarly, D’Avella et al evaluated 304 patients with solid malignancies treated with ICIs, including 54 who received at least one unit of ES transfusion within three months of immunotherapy initiation. Their results showed inferior PFS and OS among transfused patients, both in the overall population and in the NSCLC subgroup, which constituted the majority of their cohort (272 patients, 89.5%).⁴³ These findings are in line with our observations and further support the detrimental influence of peritherapeutic transfusions on ICI outcomes. In contrast to these broader analyses, our study focused exclusively on patients with NSCLC receiving nivolumab monotherapy, providing a more homogeneous population that strengthens the validity of our findings regarding the adverse impact of peritherapeutic transfusions on ICI efficacy. To the best of our knowledge, our study is the first and only investigation to date evaluating the impact of ES transfusion on survival outcomes in patients with metastatic NSCLC receiving nivolumab therapy.

In a retrospective study evaluating patients with metastatic NSCLC receiving first-line CT, those who underwent blood transfusion either before or during treatment experienced earlier disease progression and poorer OS compared with patients who did not receive transfusion. Moreover, this effect was reported to be more pronounced in the adenocarcinoma subtype.⁴⁴ Although the treatment modalities differ (ICI vs. CT), the observation that blood transfusion negatively affects survival in metastatic NSCLC—and that this effect appears particularly prominent in adenocarcinoma patients—shows notable similarity to the findings of our study.

Previous studies have also emphasized the prognostic importance of systemic inflammatory and nutritional indices in patients treated with ICIs. In a meta-analysis of 15 cohort studies involving 1336 gastric cancer patients receiving ICIs, elevated NLR and PLR were associated with poorer PFS and OS.²⁷ Likewise, a meta-analysis including 13 studies with 2342 NSCLC patients demonstrated that high pre-treatment SII predicted inferior survival among those receiving ICIs monotherapy.²⁸ Another meta-analysis involving 1321 patients across 11 studies, five of which were limited to NSCLC, found that elevated CAR was associated with shorter PFS and OS.²⁹ Furthermore, in patients treated with nivolumab as second-line therapy for metastatic NSCLC, baseline and dynamic CAR levels were predictive of treatment response and long-term survival.³⁰ Similarly, Tanaka et al reported that PD-L1 expression, PNI, and the lung immune prognostic index were significantly correlated with both PFS and OS in 237 NSCLC patients receiving ICIs, particularly in those treated with chemoimmunotherapy (CIT).³¹ Another meta-analysis including 12 studies (7 involving NSCLC) and 1359 patients demonstrated that higher PNI levels were associated with improved OR and disease control rates, whereas lower PNI levels correlated with shorter PFS and OS.³² The results of these studies align with our findings, reinforcing the prognostic value of inflammatory and nutritional markers in ICI-treated NSCLC populations.

Evidence from surgical oncology also supports an adverse impact of blood transfusion on cancer outcomes. Cata et al demonstrated that perioperative blood transfusion was independently associated with worse OS in patients undergoing surgical resection for NSCLC. Furthermore, multivariable analysis revealed a relationship between the number of transfused units and both recurrence-free survival (RFS) and OS.⁴⁵ In contrast, in our cohort, the number of transfused ES units during nivolumab therapy did not significantly influence survival. The discrepancy between the two studies likely reflects differences in timing and patient selection—Cata et al focused on perioperative transfusions in patients with potentially curable disease, whereas our study evaluated transfusions in metastatic patients receiving immunotherapy, in whom disease burden and treatment goals differ substantially. These differences underscore the context-dependent nature of transfusion-related effects across distinct oncologic settings.

The potential role of ABO blood group in modulating ICI outcomes has also been investigated. In a study assessing metastatic NSCLC patients treated with pembrolizumab (anti PD-1) monotherapy, blood group O was associated with superior survival compared with non-O groups. However, this effect was not observed in patients receiving CT or CIT.⁴⁶ In our study, ABO blood group type had no measurable effect on survival outcomes. This difference may be attributed to variations in PD-L1 expression levels and treatment lines between the two studies. In the study by Certa et al, all 82 patients had PD-L1 expression ≥50% and received pembrolizumab as first-line therapy, whereas in our cohort, only 15 patients (17%) had PD-L1 ≥50%, and most received nivolumab as second-line therapy (48.9%) or later. These distinctions likely influenced the observed outcomes.

To address baseline comorbidity burden, the CCI was retrospectively calculated for all patients at the time of nivolumab initiation. CCI did not differ significantly between transfused and non-transfused patients and was not independently associated with survival outcomes in univariable analyses. Nevertheless, residual confounding related to disease severity and treatment response cannot be fully excluded given the retrospective design and limited sample size.

An important methodological consideration in interpreting these findings is the potential for confounding by indication. Patients requiring ES transfusions during nivolumab therapy are likely to represent a clinically more vulnerable subgroup, with factors such as disease progression, baseline or treatment-related anemia, bone marrow suppression, infection, or poor treatment response contributing both to the need for transfusion and to adverse survival outcomes. In this context, ES transfusion should be interpreted primarily as a marker of clinical deterioration rather than a direct causal factor influencing survival. Given the limited sample size and number of events, multivariable adjustment was not feasible, and the observed associations should therefore be viewed as exploratory. Accordingly, the findings of this study should be considered hypothesis-generating and intended to inform the design of future prospective studies rather than to establish a causal relationship.

To mitigate concerns regarding time-related bias, we additionally assessed the timing of ES transfusions during nivolumab therapy. The first ES transfusion occurred early after treatment initiation (median 0.73 months), suggesting that transfusion exposure was not merely a consequence of prolonged treatment duration. Nevertheless, residual time-dependent confounding cannot be entirely excluded given the retrospective design and limited sample size.

The relatively small number of patients who received ES transfusions during nivolumab therapy, particularly within histological subgroups, represents an important limitation of this study. Accordingly, the subgroup findings should be interpreted with caution and viewed as exploratory and hypothesis-generating rather than confirmatory. While these observations provide clinically relevant signals regarding the potential interaction between transfusion exposure and immunotherapy outcomes, they require validation in larger, prospective cohorts.

Our study has several limitations. First, it was a retrospective, single-center study, which may introduce inherent selection and reporting biases. Another important limitation is our relatively small sample size. Due to the limited number of events and the restricted sample, we were unable to perform a multivariable Cox regression analysis. Therefore, we could not determine whether the factors identified as potential prognostic markers in the univariable analysis were independent risk factors. Second, due to reimbursement policies in our country, all patients received nivolumab monotherapy, and the majority received it as second-line or subsequent therapy. Additionally, some patients lacked PD-L1 results because of test availability and reimbursement constraints during the study period. As a result, the evaluation of the relationship between PD-L1 status, blood transfusion, and survival was limited by missing data. Consequently, the impact of blood transfusion in patients treated with CIT or ICI–ICI combinations could not be assessed. Third, given the retrospective nature of data collection, some cases may have incomplete information regarding AEs.

Conclusion

In conclusion, our findings suggest that ES transfusions administered during nivolumab therapy in patients with metastatic NSCLC may be associated with poorer survival outcomes, particularly among those with non-squamous histology. ES transfusions given before or after nivolumab did not appear to influence survival in our cohort. These observations raise the possibility that the timing of ES transfusion exposure may be associated with immunomodulatory effects during ICI therapy; however, due to the retrospective and single-center design of the study—as well as the limited sample size—these results should be interpreted with caution and considered hypothesis-generating. Larger, prospective, multicenter studies including mechanistic investigations are warranted to further clarify and validate these associations.

Footnotes

Acknowledgments

The authors have no acknowledgments to declare.

ORCID iD

Alper Coskun

Ethical Considerations

This study was approved by the Health Research Ethics Committee of Bursa Uludağ University (Approval Number: 2024-12/9, Approval Date: July 31, 2024).

Author Contributions

Conceptualization, A.C., and E.Ca.; methodology, A.C., E.Ca., and A.B.S.; software, Y.K., G.A., and H.O.B.; validation, A.B.S., A.D., and E.Cu.; formal analysis, A.C., and E.Ca.; investigation, A.C., E.Ca., E.T., and T.E.; resources, A.D., E.Cu., and T.E.; data curation, A.C., E.T., Y.K., G.A., and H.O.B.; writing—original draft preparation, A.C.; writing—review and editing, A.C., and E.Ca.; visualization, A.C., E.Ca., and E.T.; supervision, A.B.S., A.D., E.Cu., and T.E.; project administration, A.C., E.Ca., and T.E. All authors have read and agreed to the published version of the manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.*

Appendix

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