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The influence of salivary amylase on total amylase elevation in CML patients treated with TKI therapy: a case series of 3 patients

Tyrosine kinase inhibitor (TKI) therapy has transformed the outcome of patients with chronic myeloid leukemia (CML) from an aggressive malignancy to a chronic disease with a survival similar to unaffected individuals [1]. Pancreatitis, among a number of other side effects, has been reported on TKI therapy (Table 1), and serum amylase, in addition to lipase, are routine screening tests in the majority of clinical trials, as well as being evaluated systematically in clinical practice. Dose adjustment of the individual TKI is recommended according to the degree of such toxicities [2], and in particular, dose modifications for biochemical adverse events (AE) are stringent when patients are treated on clinical trials. TKI dose interruption and reduction is associated with a less likelihood of achieving cytogenetic responses and higher chance of treatment failure in certain patients’ groups [3,4]. It is therefore essential that any AE is appropriately attributed to TKI treatment and not to other unrelated causes. Human amylases (salivary and pancreatic) belong to the a amylase family, with 97% homology between both isoenzymes. The main clinical application of amylase differentiation remains the diagnosis of pathology in either the pancreas or salivary glands [5]. Acute pancreatitis is associated with significant mortality and morbidity, and although a raised amylase is a sensitive test for acute pancreatitis, it is not specific for this condition. Hyperamylasemia is reported in many other non-pancreatic and more benign conditions. The exact mechanism by which TKIs causes pancreatitis is unclear. Proposed mechanisms include inhibition of vascular endothelial growth factor with subsequent apoptosis of acinar cells and release of digestive enzymes, and decreased motility of the gastrointestinal tract with reflux of the digestive enzymes into the pancreatic duct leading to activation of the pancreatic enzymes [6,7]. The recent European LeukemiaNet guidelines for the management of TKI side effects have outlined recommendations for TKI dose adjustment according to the AE grade (Table 1) [2]. We report a series of three cases where serum amylase performed was sufficiently elevated for patients to interrupt TKI treatment or reduce the dose. The patients were asymptomatic and had no evidence of pancreatic disease, and in all three patients, we found that the amylase elevation was due to the increase in the salivary rather than the pancreatic isoenzyme. Patient 1 was diagnosed with CML in chronic phase (CP) in 2007, treated with imatinib 400mg, and achieved stable molecular response (MR; RT qPCR for BCR-ABL1 of 0.008% ). Elevated serum amylase (grade 1) was incidentally detected in 2016 as part of preoperative evaluation for laryngeal polypectomy; however, serum lipase was within normal limits. Despite reducing the dose of imatinib to 300mg daily, serum amylase remained elevated (grade 1), while the molecular response was maintained at MR. Quantification of the pancreatic isoenzymes revealed predominant elevation of the salivary isoenzyme. Consequently, no further action was required and the patient remained asymptomatic throughout (Table 2). Patient 2 was diagnosed with CML-CP in 2014 and initially treated with imatinib 400mg, but due to haematological toxicity, changed to nilotinib. Nilotinib was discontinued due to hepatotoxicity and abdominal pain. Investigations included serum amylase, which was found to be elevated (grade 3). Following the introduction of a lower starting dose of dasatinib for tolerance, the amylase remained elevated (grade 2) in the absence of clinical symptoms forcing interruption of therapy. Amylase elevation persisted after discontinuing dasatinib, and was found to be mainly salivary isoenzyme elevation (59%). As a result, therapy was switched to bosutinib. Serum amylase however continued to be elevated (grade 2) which was principally an increase in salivary isoenzyme. Only a minor increase in serum lipase was detected (grade 1). Computed tomography (CT) of the abdomen revealed no pancreatic abnormality, otolaryngology was unremarkable, and endoscopy only showed mild reflux