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Abstract

BACKGROUND:

The relationship of the ABO blood group system with the immune response is known, but its relationship with immune checkpoint inhibitors (ICIs) has not been clearly investigated until now.

OBJECTIVE:

In this study, the relationship between different blood groups and nivolumab treatment response in patients with advanced malignant melanoma was investigated.

METHODS:

The data of patients who used nivolumab for advanced malignant melanoma between April 2018 and April 2021 were retrospectively reviewed.

RESULTS:

A total of 73 patients were included in the study. In the progression-free survival (PFS) analysis according to blood groups, it was 3.9 months, 16.1 months, 20.0 months and 3.0 months for A, B, AB and O, respectively ( $p=$ 0.1). Overall survival (OS) analysis according to blood groups was 5.1 months, 25.0 months, 20.0 months and 9.3 months for A, B, AB and O, respectively ( $p=$ 0.1). The B antigen group (B or AB) had significantly longer PFS and OS than the non-B antigen group (A or O) (16.1 vs. 3.5 months for PFS, respectively, $p=$ 0.03; 20.0 vs. 7.4 months for OS, respectively, $p=$ 0.02).

CONCLUSIONS:

The presence of B antigen provides a significant advantage in terms of survival in patients using ICIs for advanced melanoma.

Keywords

Immune checkpoint inhibitor nivolumab ABO blood group predictive biomarker

1. Introduction

Melanoma is a skin cancer with one of the worst prognoses. It is the fifth most common cancer in men and women in the USA and its incidence increases with age [1]. Most cases of malignant melanoma are diagnosed at an early stage, when surgical excision can be curative. However, immunotherapies, targeted agents, and cytotoxic chemotherapy are needed in the treatment of advanced melanoma. Immune checkpoint blockade induces response and provides unique clinical benefits in advanced melanoma treatment. Promising results have been obtained in treatment with immune checkpoint inhibitors (ICIs) such as programmed cell death-1 (PD-1) inhibitors (pembrolizumab and nivolumab) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) inhibitors (ipilimumab). In addition, targeted therapies (BRAF plus MEK inhibitors) also prolong progression-free and overall survival compared to chemotherapy. However, treatment success is prevented by the high resistance to anti-PD-1 agents seen in advanced metastatic melanoma.

ABO blood group antigens are expressed in various tissues. Specific ABO blood groups are easily observed parameters that have been reported to be associated with the increased incidence of different tumor types. Previous studies showed a relationship between ABO blood groups and malignancies such as hepatocellular carcinoma and gastric and pancreatic cancer [2, 3, 4]. The relationship between blood types and the incidence of malignant melanoma has been investigated before and there are conflicting data. However, the relationship between ABO blood groups and immunotherapy response in cancer treatment is full of unknowns. To the best of our knowledge, the relationship between blood groups and ICIs’ response in malignant melanoma has not been investigated so far. In the present study, the relationship between different blood groups and nivolumab treatment response in patients with advanced malignant melanoma was investigated.

2. Materials and methods

The data of patients using nivolumab with a diagnosis of advanced stage, unresectable malignant melanoma and followed up in 5 different oncology centers in Turkey between April 2018 and April 2021 were reviewed retrospectively. In accordance with the health policies in this country, in order to use nivolumab in the treatment of malignant melanoma, there is a prerequisite to receive one line treatment (chemotherapy or BRAF/MEK inhibitors). It can also be used as a single agent only. Therefore, our patient population consists of patients who received at least one line of treatment and then used nivolumab as a single agent.

Age 18 years or older, histologically proven cutaneous malignant melanoma, Eastern Cooperative Oncology Group (ECOG) performance status 0–1 or 2, measurable unresectable metastatic disease according to the Immune Response Evaluation Criteria in Solid Tumors (iRECIST), and ABO blood group known patients were included in the study. In addition to those who did not meet the inclusion criteria, patients with brain metastases and second primary cancer were excluded from the study.

Age, sex, smoking status, ECOG performance status, BRAF mutation status, number of metastases, metastatic site localization, treatment line using nivolu-mab, ABO and RH blood groups, and hemogram and biochemical parameters were recorded from the patient files. Toxicity analysis could not be performed due to insufficient toxicity data.

Nivolumab was given at a dose of 3 mg/kg (max dose 240 mg) every 2 weeks. All patients underwent a physical examination and hematological and biochemical evaluations every 2 weeks in the first cycle and then on the first day of each cycle. Tumor response was assessed by computed tomography (CT) or positron emission tomography (PET)/CT every 12 weeks according to iRECIST criteria.

2.1 Prognostic and predictive factor analysis

Nine variables that may have an impact on survival were selected. The variables were divided into two categories: age ( $<$ 55 or $\geqslant$ 55 years), sex (male or female), smoking (yes or no), ECOG-PS (0–1 or 2), BRAF mutation status (mutant or wild), number of metastatic sites (1 or $\geqslant$ 2), Rh factor (Rh+ or Rh-), lactate dehydrogenase (LDH) (normal or high), and neutrophil-to-lymphocyte ratio (low or high). The cut-off value for age 55 years was calculated according to the median value. Since the number of patients was small, they were divided into 2 groups (B/AB and A/O) according to the presence of the B antigen in order to enable a more homogeneous analysis.

2.2 Statistical analysis

Table 1
Baseline characteristics of all patients

	N: 73
Age, median (range)	55	(18–90)
$<$ 65 years	44	(60%)
$\geqslant$ 65 years	29	(40%)
Sex
Female	40	(55%)
Male	33	(45%)
Smoking
No	46	(63%)
Yes	27	(37%)
ECOG performance status
0–1	53	(73%)
0.2	20	(27%)
ABO blood group
A	38	(52%)
B	18	(25%)
AB	2	(3%)
O	17	(20%)
Rhesus (Rh) factor
Rh+	63	(86%)
Rh-	10	(14%)
BRAF mutation
Wild	56	(76%)
Mutant	17	(24%)
Number of metastatic sites
Multiple	46	(63%)
Single	27	(37%)
Line using nivolumab
Second line	58	(80%)
Third line	9	(12%)
Fourth line	6	(8%)
LDH (U/L) (median)	235
Albumin (g/dL) (median)	3.8
Hemoglobin (g/L) (median)	12
Neutrophil-to-lymphocyte ratio (median)	3.18

ECOG: Eastern Cooperative Oncology Group, LDH: Lactate Dehydrogenase.

The statistical analysis was performed using the Statistical Package for the Social Sciences Version 22.0 for Windows (SPSS Inc., Chicago, IL, USA). Comparison of the 2 groups was performed by Mann-Whitney U test and Pearson chi-square or Fisher test for continuous and categorical variables, respectively. Survival analysis was analyzed by the Kaplan-Meier method using the log-rank test. Survival times were determined in the 95% confidence interval (CI) range. $p<$ 0.05 was considered statistically significant. The factors that were significant in the univariate analysis were evaluated by multivariate analysis. The Cox regression test was used for multivariate analysis.

Overall survival (OS) was calculated from the day of receiving analyzed treatments to death or the last visit. The time to disease progression or death from any cause was calculated as progression-free survival (PFS).

Table 2

Patient characteristics by B antigen status

Non-B antigen (A/O) (n:53)

B antigen (B/AB) (n:20)

p

- value

Age, median (range)

52 (25–85)

57 (18–90)

0.4

<

55 years

24 (45%)

11 (55%)

\geqslant

55 years

29 (55%)

9 (45%)

Sex

0.5

Female

28 (53%)

12 (60%)

Male

25 (47%)

8 (40%)

Smoking

0.3

32 (61%)

14 (70%)

Yes

21 (39%)

6 (30%)

ECOG performance status

0.8

0–1

39 (74%)

14 (70%)

0.2

14 (26%)

6 (30%)

BRAF mutation

0.3

Wild

39 (74%)

17 (85%)

Mutant

14 (26%)

3 (15%)

Number of metastatic sites

0.3

Multiple

35 (66%)

12 (60%)

Single

18 (34%)

8 (40%)

Line using nivolumab

0.8

Second line

43 (81%)

15 (75%)

Third line

6 (11%)

3 (15%)

Fourth line

4 (8%)

2 (10%)

LDH (U/L) (median)

235

252

0.4

Albumin (g/dL) (median)

3.8

3.7

0.6

Hemoglobin (g/L) (median)

11.9

0.8

Neutrophil-to-lymphocyte

ratio (median)

2.92

3.87

0.1

ECOG: Eastern Cooperative Oncology Group, LDH: Lactate Dehydrogenase.

3. Results

3.1 Patient characteristics

A total of 73 patients were included in the study. The median age of all patients was 55 years (range 18–90), and 55% ( $n=$ 40) were female. Eighty percent ( $n=$ 58) of the patients used nivolumab in the second line. BRAF mutation was present in 24% ( $n=$ 17) of the patients. All BRAF mutant patients had received a BRAF/MEK inhibitor combination and 56 patients with BRAF wild used temozolomide in the first line treatment. Of the patients, 52% ( $n=$ 38) had blood group A, 25% ( $n=$ 18) B, 3% ( $n=$ 2) AB, and 20% ( $n=$ 17) O. The basal characteristics of the patients are given in Table 1.

Figure 1.

Kaplan-Meier survival curves by ABO blood group; (A) overall survival, (B) progression-free survival.

3.2 Survival results

The median follow-up period of the study was 9.4 months. The median duration of nivolumab use was 2.7 months in group A, 11.4 months in group B, 14.2 months in group AB, and 2.4 months in group O. The median PFS for all patients was 5.9 months and OS was 11.7 months. In the PFS analysis according to blood groups, it was 3.9 months, 16.1 months, 20.0 months, and 3.0 months for A, B, AB, and O, respectively ( $p=$ 0.1). OS analysis according to blood groups was 5.1 months, 25.0 months, 20.0 months and 9.3 months for A, B, AB, and O, respectively ( $p=$ 0.1). The presence of the B antigen (B or AB) appeared to be associated with longer PFS and OS. The survival curves are given in Fig. 1. Ten patients were Rh negative and when subgroup analysis was performed according to the Rh factor, it was seen that the Rh factor did not create a survival difference in any blood group.

3.3 Patient characteristics according to the presence of the B antigen

There were 20 patients in the B antigen group (B/AB) and 53 patients in the non-B antigen group (A/O), and there was no difference between the groups in terms of baseline characteristics. Patient characteristics according to the presence of the B antigen are given in Table 2.

3.4 Tumor response rates according to the presence of the B antigen

The tumor response status of 1 patient in the B antigen group could not be established, and the response rates of 19 patients in that group and all patients in the non-B antigen group were evaluated. The objective response rate in the B antigen group was significantly higher than that in the non-B antigen group (68% vs. 27%, respectively, $p=$ 0.001). Tumor response rates are detailed in Table 3.

Table 3
Tumor response rate

	Non-B antigen (n:53)	B antigen (n:19)	$p$ -value
CR	2 (4%)	1 (5%)	0.80
PR	12 (23%)	12 (63%)	0.001
SD	12 (23%)	1 (5%)	0.08
PD	27 (51%)	5 (26%)	0.05
Objective response rate	27%	68%	0.001

CR $=$ Complete Response, PR $=$ Partial Response; SD $=$ Stable Disease; PD $=$ Progressive Disease.

3.5 Survival outcomes by presence of the B antigen

The B antigen group had significantly longer PFS than the non-B antigen group (16.1 months vs. 3.5 months, respectively, $p=$ 0.03). In terms of OS, the B antigen group had significantly longer OS than the non-B antigen group (20.0 months vs. 7.4 months, respectively, $p=$ 0.02). The survival curves are given in Fig. 2. In the B antigen group, when the subgroup analysis was performed according to the Rh factor (16 patients were Rh positive and 4 patients were Rh negative), although both PFS and OS were longer in the Rh-positive patients, the difference was not statistically significant (OS was 20.0 months vs. 8.1 months, $p=$ 0.9; PFS was 16.3 months vs. 3.5 months, $p=$ 0.15).

3.6 Univariate and multivariate analysis results according to the presence of the B antigen

In the univariate analysis for PFS, age below 55 (12.8 months vs. 3.2 months, $p=$ 0.002), ECOG performance status being 0–1 (10.3 months vs. 3.0 months, $p<$ 0.001), having a single number of metastatic sites (12.8 months vs. 3.5 months, $p=$ 0.01), and normal LDH value (14.8 months vs. 3.4 months, $p<$ 0.001) were good prognostic factors but the presence of the B antigen was not. When these factors were evaluated in the multivariate analysis, the presence of the B antigen was found to be an independent prognostic factor for PFS (HR $=$ 0.29, 95% CI $=$ 0.14–0.60, $p=$ 0.001) (Table 4).

Table 4
Univariate and multivariate analysis of progression-free survival

Variable

Univariate analysis

for PFS (median, months)

p

-value

Multivariate analysis

Age

0.002

=

0.53, 95% CI

=

0.30–0.95,

p=

0.03

<

55 years

12.8

\geqslant

55 years

3.2

Sex

0.2

Female

9.3

Male

4.6

Smoking

0.2

4.6

Yes

9.3

ECOG performance status

<

0.001

=

0.47, 95% CI

=

0.23-0.94,

p=

0.03

0–1

10.3

0.2

3.0

BRAF mutation

0.6

Wild

5.9

Mutant

4.7

Number of metastatic sites

0.01

=

0.65, 95% CI

=

0.35–1.22,

p=

0.1

Multiple

3.5

Single

12.8

Lactate Dehydrogenase (LDH)

<

0.001

=

0.35, 95% CI

=

0.18–0.67,

p=

0.001

<

235 U/L

14.8

\geqslant

235 U/L

3.4

Neutrophil-to-lymphocyte ratio

0.2

<

3.18

7.3

\geqslant

3.18

4.0

Rhesus (Rh) factor

0.2

Rh+

7.3

Rh-

3.5

B antigen status

0.03

=

0.29, 95% CI

=

0.14–0.60,

p=

0.001

B antigen (B/AB)

16.0

Non-B antigen (A/O)

3.5

PFS $=$ Progression-free survival, ECOG: Eastern Cooperative Oncology Group, HR $=$ Hazard Ratio, CI $=$ confidence interval.

Figure 2.

Kaplan-Meier survival curves by B blood group antigen; (A) overall survival, (B) progression-free survival.

Table 5

Univariate and multivariate analysis of overall survival

Variable

Univariate analysis for

PFS (median, months)

p

-value

Multivariate analysis

Age

0.001

=

0.55, 95% CI

=

0.29–1.01,

p=

0.06

<

55 years

20.0

\geqslant

55 years

5.1

Sex

0.1

Female

13.5

Male

9.4

Smoking

0.2

9.8

Yes

13.5

ECOG performance status

<

0.001

=

0.32, 95% CI

=

0.16–0.66,

p=

0.002

0–1

20.0

0.2

3.7

BRAF mutation

0.7

Wild

11.7

Mutant

9.4

Number of metastatic sites

0.005

=

0.55, 95% CI

=

0.26–1.17,

p=

0.1

Multiple

6.4

Single

25.0

Lactate Dehydrogenase (LDH)

<

0.001

=

0.32, 95% CI

=

0.16–0.64,

p=

0.001

<

235 U/L

25.8

\geqslant

235 U/L

5.1

Neutrophil-to-lymphocyte ratio

0.3

<

3.18

13.6

\geqslant

3.18

9.4

Rhesus (Rh) factor

0.7

Rh+

11.7

Rh-

9.3

B antigen status

0.02

=

0.23, 95% CI

=

0.10–0.53,

p=

0.001

B antigen (B/AB)

20.0

Non-B antigen (A/O)

7.4

OS $=$ Overall survival, ECOG: Eastern Cooperative Oncology Group, HR $=$ Hazard Ratio, CI $=$ confidence interval.

In the univariate analysis performed in terms of OS, age, ECOG performance status, number of metastatic sites, and LDH value were determined as prognostic factors but the presence of the B antigen was not. When these factors were evaluated in the multivariate analysis, the presence of the B antigen was found to be an independent prognostic factor for OS as well as PFS (HR $=$ 0.23, 95% CI $=$ 0.10–0.53, $p=$ 0.001) (Table 5).

4. Discussion

To the best of our knowledge, this is the first study to examine the presence of different blood group antigens and the response to immunotherapy. According to our findings, in patients with advanced malignant melanoma, patients with a blood group containing the B antigen respond better to ICIs and survival is significantly longer.

In previous studies examining the relationship between blood group and malignant melanoma, blood group A was found to be associated with the incidence of cutaneous malignant melanoma. Moreover, patients with blood group A were more likely to experience metastasis in cutaneous malignant melanoma, whereas this association was not detected in groups AB and B [5]. In another study, a positive correlation was found between O blood type and the incidence of malignant melanoma [6]. In contrast, two other studies show that blood group O prevents tumor spread [7, 8]. A study in patients with ovarian cancer showed that patients with blood group B had worse survival than those with non-B blood groups [9]. In addition, survival was worse in the B antigen group (B/AB) and the non-B antigen (A/O) group. A non-O blood group was shown to be associated with reduced OS in 900 patients undergoing resection for renal cell carcinoma [10]. No correlation was found between the blood group and prognosis of 404 patients who underwent resection for esophageal carcinoma [11].

The confusing relationship between immunotherapy and blood groups has been speculated about for a long time. In a short communication written in 1981, it was thought that levamisole, which was used as an antiparasitic agent and immunostimulant in the treatment of primary lung cancer at that time, achieved this effect by increasing the Th1 lymphocyte-related immune response and decreasing the Th2 lymphocyte-related response [12]. Lung cancer patients with O or Rh-negative blood groups treated with levamisole had significantly reduced overall survival. Furthermore, Rh-negative patients showed worse survival than Rh-positive patients. In our study, although survival was numerically worse in the Rh-negative patients in the B antigen group, the difference was not statistically significant. The reason it did not reach statistical significance may have been the small number of patients.

PROSTVAC-VF, a cancer vaccine, is an immunotherapy undergoing phase III clinical studies for the treatment of advanced prostate cancer [13]. It was found that patients with blood group B (median 38 months) and O (median 27.6 months) are associated with longer median survival than patients with group A (median 15.8 months) and AB (median 21.7 months) [14]. The low number of patients in that study, especially those with B and AB blood groups, may complicate the evaluation. Similar to that study, the presence of B antigen (B/AB) was associated with longer PFS and OS and objective response rate in our study. However, prospective studies with larger number of patients with different cancer types are needed to clearly explain this situation.

Blood group antigens are found on receptors such as integrins, cadherins, epidermal growth factor, and CD44 that control cell proliferation, resistance to apoptosis, and adhesion [15]. Inhibition of integrin in cancer cells results in local PD-L1 reduction and reduction in primary tumor growth [16]. Different blood group antigens, especially expressed on integrin, may decrease PDL-1 production differently by an unknown mechanism and may cause a different response to immunotherapy. Blood group antigens may also play a role in the effect of inflammation-soluble intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor alpha (TNF- $\alpha$ ) in plasma [17, 18]. In a preclinical melanoma model, TNF- $\alpha$ facilitated tumor growth by acting through the TNFR1 pathway, disrupting the infiltration of CD8+T lymphocytes into the tumor microenvironment [19]. TNFR1 blockade enhances the efficacy of anti-PD-1 therapy. Preventing TNF- $\alpha$ upregulation of PDL-1 expression by CD8+ tumor infiltrating lymphocytes causes reappearance of anti-tumor immune response and prevents anti-PD-1 resistance [20]. Although the mechanism of action is unknown, the different effects of ABO blood group antigens on the TNF- $\alpha$ response may affect the relationship between TNF- $\alpha$ and PDL-1 at different rates, thereby changing the response to immunotherapy. However, these hypotheses need to be clarified by experimental studies.

Approximately one-half of cutaneous melanomas have a V600 mutation in the BRAF gene. In our study, the BRAF mutation rate was 24%. This difference may have been due to geographical and ethnic differences. In patients with BRAF V600 mutation-negative, stage IV melanoma, PD-1 inhibitor monotherapy or a combination of nivolumab and ipilimumab are the preferred options for immunotherapy. Clinical studies are needed to determine which disease subgroups benefit more from the combination versus monotherapies and what the optimal dose and schedule for the combination is. Immunotherapy is used in the BRAF V600 mutation-positive patient group because of its ability to provide long-term treatment-free survival. However, studies are needed to determine the optimal treatment sequence in this patient group. Although the efficacy of immunotherapy appears to be less after progression with a BRAF inhibitor, prospective data are needed for combination therapy or monotherapy in this situation. In the present study, all BRAF mutant patients had received a BRAF/MEK inhibitor combination and BRAF wild patients used temozolomide in the first line treatment. There was no difference in OS or PFS for immunotherapy between the BRAF mutant and non-mutant group.

Although our study was the first to examine the immunotherapy response with ABO blood groups, it had some limitations. The most important limitation of the study was that it was retrospective. The number of patients was relatively small. Especially the presence of two patients with the AB blood group made the evaluation difficult. In addition, due to the health policies in this country, nivolumab treatment was used in the second line at the earliest. Patients who received nivolumab treatment in the third and fourth lines were also included in the study. However, due to the small number of patients in the subgroups, a comparison between the different treatment lines was not possible.

5. Conclusion

In the present study, we aimed to draw attention to the relationship between blood groups and immunotherapy responses in advanced melanoma patients treated with nivolumab. Presence of the B antigen in advanced stage melanoma patients was an important advantage in terms of survival. Certain estimates have been made for the underlying mechanism. However, prospective studies are needed to reveal the clear mechanism and to determine the ABO blood group-immunotherapy response in different cancer types. Our study will guide other studies in this respect.

Footnotes

Acknowledgments

This study was approved by our Institutional Ethics Committee and was conducted according to the principles of the Declaration of Helsinki. (Decision Date: 26/05/2021 Decision No: E1-21-1799).

Conflict of interest

All authors have declared no conflicts of interest.

Authors’ contributions

Conception: YE, EEG.

Interpretation or analysis of data: YE, MB, GU, ZK, ZU, ES, TE, VA, SK, YA, MD.

Preparation of the manuscript: YE, SAE, İE, EEG.

Revision for important intellectual content: YE, MD, DU.

Supervision: DU.

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Predictive and prognostic effect of ABO blood group on immune checkpoint inhibitors

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

2. Materials and methods

2.1 Prognostic and predictive factor analysis

2.2 Statistical analysis

Table 1 Baseline characteristics of all patients

3.1 Patient characteristics

3.3 Patient characteristics according to the presence of the B antigen

3.4 Tumor response rates according to the presence of the B antigen

Table 3 Tumor response rate

3.6 Univariate and multivariate analysis results according to the presence of the B antigen

Table 4 Univariate and multivariate analysis of progression-free survival

5. Conclusion

Footnotes

Acknowledgments

Conflict of interest

Authors’ contributions

References

Table 1
Baseline characteristics of all patients

Table 3
Tumor response rate

Table 4
Univariate and multivariate analysis of progression-free survival