Haemoglobin level increase as an efficacy biomarker during axitinib treatment for metastatic renal cell carcinoma: a retrospective study

Renal cancer represents 2–3% of all cancers, with an increased incidence in Western countries. The most common form is renal cell carcinoma (RCC) and approximately 30% of patients will present metastatic disease (mRCC) [ 1]. Better insight into the molecular pathways involved in RCC has spurred the development of novel targeted therapies. One such pathway involves loss of function of the von Hippel-Lindau (VHL) tumour-suppressor gene leading to vascular endothelial growth factor (VEGF) overexpression, which promotes neo-angiogenesis [ 2]. Molecular agents targeting angiogenesis, such as anti-VEGF monoclonal antibodies and tyrosine kinase inhibitors (TKI) acting on the VEGF receptor (VEGFR), have become a standard of care in mRCC.

The TKI axitinib is an oral, potent, and selective VEGFR-1, −2, and −3 inhibitor, used after failure of a prior first-line treatment with cytokines or sunitinib for the treatment of mRCC. Common side effects associated with axitinib are high blood pressure (hBP), diarrhoea, fatigue, decreased appetite, nausea, and dysphonia [ 3, 4]. Studies have shown that some adverse effects, such as the onset of hBP, are correlated to treatment efficacy [ 5, 6].

In the phase III study AXIS, which compared axitinib ( n = 361) with sorafenib ( n = 362) as second-line therapy in 723 patients with mRCC, 10% of patients treated with axitinib presented elevated haemoglobin, requiring phlebotomy in three patients. Several other cases of early haemoglobin level increase during various antiangiogenic treatments have been reported since. These increases appeared a few weeks after treatment initiation and seemed associated with better outcomes [ 7– 11].

Based on these observations, we performed a retrospective analysis to determine whether early haemoglobin level increase during axitinib treatment in mRCC is associated with better prognosis.

Our study suggests that an increase in haemoglobin level in the first three months of axitinib treatment is associated with longer PFS, implying that such increases could be an early indicator of drug activity. When combining HbL increase with hBP, this association becomes a stronger predictor of PFS than either factor alone. HbL increase could thus be an additional early biomarker of treatment efficacy, complementary to radiological evaluations, and appearing in most cases before the radiological evaluations which are typically performed at three months of treatment. Two of our patients with early HbL increase presented delayed partial responses to axitinib, suggesting axitinib be continued in cases with early HbL increase, in the absence of dose-limiting toxicities or progressive disease.

To our knowledge, this is the largest retrospective study of axitinib-induced haemoglobin changes. High BP is already known as a marker of axitinib efficacy [ 6], but the fact that haemoglobin elevation could be a simple, early efficacy biomarker predictive of outcome is novel. These findings are in agreement with previous published cases reporting increased HbL associated with several VEGF inhibitors, including bevacizumab, sunitinib, sorafenib, and axitinib [ 7– 11]. In most cases, erythropoiesis developed in the first month after treatment initiation and was reversible at treatment discontinuation. Some of these cases report transient erythropoietin (EPO) increases [ 10, 11]. Bhatta et al. retrospectively analysed several trials with VEGF inhibitors and found a correlation between VEGF inhibitor exposure, increased EPO, and red blood cell counts, independently of blood pressure or creatinine clearance changes [ 16]. Although the physiopathology of this haemoglobin increase is not yet fully understood, EPO is likely to play a part. A hypothesis explaining axitinib-related haemoglobin elevation is that VEGF blockage induces rebound erythrocytosis by stimulating hypoxia-inducible factors such as EPO. Tam et al. found that VEGFR-2 inhibition by aflibercept in animal models lead to hepatic EPO production and erythrocytosis detectable after 4 weeks of treatment [ 17]. In cases with normal or diminished EPO levels, authors suggested increased sensitivity to EPO due to TKI treatment as a possible mechanism [ 8]. Many disease-related factors such as inflammation, tumour bleeding or malnutrition may have favoured anaemia in some of our patients. Axitinib could have corrected anaemia by decreasing tumour volume, thus leading to HbL increase. It is unlikely that the increase in HbL was paraneoplastic as it was temporally related with treatment administration and associated with better objective responses and longer PFS. EPO levels, VHL mutational status, and JAK2V617F status were not available for most patients in this study.

Polycythaemia, defined by revised WHO criteria [ 12], was not correlated to outcome, although the small number of cases limits statistical power. The polycythaemia criteria were perhaps too stringent. The gold standard for diagnosis is isotopic red cell mass measurement (RCM) and there is debate over whether haemoglobin or haematocrit levels alone can substitute for RCM. In the polycythaemia group, baseline haemoglobin before axitinib initiation was higher and this has been shown to be a favourable prognostic factor [ 18]. Also, polycythaemia management was not standardized with dose reduction for three patients while others continued on full-dose therapy, which could account for differences in outcome. We cannot draw definitive guidelines for polycythaemia management on axitinib treatment from this analysis, but our results encourage us to continue axitinib with concomitant symptomatic treatment.

The PFS observed in our study are not comparable to those of the main phase III axitinib study (AXIS) as we excluded patients who had received less than three months of treatment, thus removing from our analysis many patients with short PFS [ 4]. Interestingly, 31% of patients received axitinib beyond the 3rd line of treatment, a situation for which very few data are available.

Our study was limited by its retrospective design, precluding complete data collection, but this was compensated by standardized data collection, patient referral through the GETUG network, and rigorous selection criteria, with the exclusion of patients with insufficient data.

The use of the median as an arbitrary cut-point for the study of the continuous variable HbL, while allowing for a simple, practical biological threshold, reduces statistical power [ 19].

We cannot control for the possibility that anaemia present at baseline in certain patients was due to prior therapy and that haemoglobin normalization during axitinib treatment was only due to washout of the previous treatment.

The absence of impact of HbL increase alone on OS could be due to following lines of treatment, which were not controlled for. Occurrence of hBP in patients with HbL increase raises questions about the complementary link between both factors. Some authors suggest the two are correlated and due to a decrease in nitric oxide production by VEGFR inhibition, leading to loss of plasma volume [ 10]. This may explain why both factors together were associated with better outcomes than each factor considered individually.

This retrospective study suggests that early haemoglobin level increase during axitinib treatment in patients with metastatic renal cell carcinoma is associated with significantly improved clinical outcome. When combined with elevated blood pressure, it is a stronger predictive factor of better outcome than either factor considered separately. This easily manageable and measurable potential adverse event biomarker requires prospective validation.