Prolactin as a biomarker for chronic GvHD

Prolactin is a hormone and cytokine secreted from the anterior pituitary gland, that is best known for its role in stimulating milk production. However, it is also produced by other cells such as neurons, epithelium, and immune cells influencing Th1 and Th2 immune responses, and modulating the function of B cells and T cells by acting as a growth and survival factor. Prolactin can enhance immunoglobulin production by B lymphocytes, and dysregulation of prolactin can promote autoimmunity. Hyperprolactinemia has previously been reported in patients with graft-versus-host disease (GvHD); however, its correlation with GvHD activity has not been explored in detail.¹

Maria Queralt Salas and colleagues investigated if prolactin can be used as a biomarker for chronic GvHD (cGvHD) activity. The results of this retrospective analysis were recently published in the European Journal of Haematology.¹ 

Study design and patient characteristics¹

• Analysis included 316 patients who underwent an allogeneic hematopoietic stem cell transplant (allo-HSCT) at the Princess Margaret Cancer Centre, Toronto, CA, between 2010–2016, and survived > 1 year. All patients underwent standard annual evaluation as part of routine clinical practice after allo-HSCT.
• Acute GvHD was graded according to the Keystone criteria and cGvHD was graded according to the National Institutes of Health (NIH) criteria.
• Baseline patient characteristics can be seen in Table 1.
  • The most prevalent transplant indication was a diagnosis of acute myeloid leukemia (42.7% of patients).
  • The median follow-up time was 4.7 years (range, 1–9.8 years)

Table 1. Baseline patient characteristics¹

Characteristic	% of patients (N = 316)
ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelomonocytic leukemia; GvHD, graft-versus-host disease; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; MRD, matched related donor; MUD, matched unrelated donor.
Median age (range)	53 (19–71)
Sex, male/female	51.3/48.7
Diagnosis
AML	42.7
ALL	10.7
MDS	12.6
MPN	10.1
CML	5.4
CLL	10.7
T-prolymphocytic leukemia	0.6
Severe aplastic anemia	2.9
Other	1.2
Donor type
10/10 MRD	44.9
10/10 MUD	41.8
9/10 MUD	12.0
Haploidentical donor	1.3
Intensity of conditioning regimen
Myeloablative	60.1
Reduced intensity	39.9
GvHD prophylaxis
T-cell depletion	47.5
No T-cell depletion	52.5
Source of graft
Bone Marrow	5.7
Peripheral Blood	94.3

As primary hypothyroidism and renal impairment can influence prolactin levels, thyroid stimulating hormone (TSH) levels and kidney function were assessed in this patient population.

Results

Overall¹

• 14.5% of patients relapsed and 24.4% died.
• 2- and 5-year overall survival were 86.8% and 77.4%, respectively.
• 74.7% of patients had cGvHD
  • The grade was moderate or severe in 63% of patients
• Two patients developed renal impairment (chronic kidney injury with creatinine elevation) which was due to active renal cGvHD.

1 year after allo-HSCT¹

• 21% of patients had active cGvHD
• 19.9% of patients had hyperprolactinemia (Table 2)
  • Of these patients 15.9% also had elevated TSH

Table 2. Prolactin and TSH assessment 1 year after allo-HSCT¹

Result	Total population (N = 316)	Active cGvHD (n = 65)	Non-active cGvHD (n = 251)	p value
allo-HSCT, allogeneic hematopoietic stem cell transplant; cGvHD, chronic graft-versus-host disease; TSH, thyroid stimulating hormone.
Prolactin level, %
Normal	80.1	49.2	88	< 0.001
Elevated	19.9	50.8	12
TSH level, %
Normal	89.9	86.2	91.2	0.224
Elevated	10.0	13.8	8.8

• The proportion of patients with hyperprolactinemia was greater for those with active cGvHD compared with those with non-active cGvHD (50.8% vs 12%; p < 0.001)
• Increasing levels of prolactin were associated with a higher probability of presenting with severe active cGvHD (Odds ratio [OR], 1.03; 95% CI, 1.01–1.05; p = 0.033) but not with being diagnosed with de novo cGvHD (OR, 0.99; 95% CI, 0.95–1.03; p = 0.801)
• Multivariate analysis (Table 3) showed:
  • hyperprolactinemia correlated with cGvHD activity; patients with hyperprolactinemia were 6.9 times more likely to have active cGvHD compared with those with normal levels of prolactin (p < 0.001).
  • receiving T-cell depletion for GvHD prophylaxis reduced the chance of having active cGvHD at 1 year after allo-HSCT (p = 0.001).

Table 3. Multivariate analysis of characteristics associated with active cGvHD¹

Variable	Odds ratio	95% CI	p value
cGvHD, chronic GvHD; CI, confidence interval; TSH, thyroid stimulating hormone; GvHD, graft-versus-host disease.
Prolactin levels (elevated vs normal)	6.94	3.6–13.1	< 0.001
TSH levels (elevated vs normal)	1.51	0.58–3.90	0.389
T-cell depletion for GvHD prophylaxis (with vs without)	0.34	0.18–0.66	0.001

• There was no correlation between prolactin levels and survival outcomes in patients with active cGvHD.

Conclusions

Prolactin may serve as a biomarker for activity of cGvHD as patients with hyperprolactinemia were ~7 times more likely to have active cGvHD compared with those with normal levels of prolactin. However, further studies are needed to confirm these findings and explore if prolactin has a role in regulating Th1 and Th2 immune responses in the development of GvHD or is simply a consequence of B-cell and T-cell activation.

This study is limited by its retrospective nature and because prolactin levels were only analyzed annually. Therefore, prospective studies assessing prolactin levels during the development and resolution of cGvHD are required to confirm if prolactin can be used as a biomarker for active cGvHD.