Recurrent hyperglycemic hyperosmolar state after re-administration of dose-reduced ceritinib, an anaplastic lymphoma kinase inhibitor

Abstract

Ceritinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor with clinical activity in crizotinib-resistant ALK-positive non-small cell lung cancer and in treatment-naïve ALK-positive disease. Hyperglycemia is a known adverse event, but the mechanism by which ceritinib causes hyperglycemia is unknown, and whether ceritinib causes hyperglycemic emergencies is unclear. Here, we report the case of a patient with a hyperglycemic hyperosmolar state (HHS) recurrence after the re-administration of dose-reduced ceritinib. A 78-year-old man with type 2 diabetes diagnosed as having advanced lung adenocarcinoma had been treated with alogliptin (25 mg/day) for the diabetes and with ceritinib for the lung cancer. After 28 days of ceritinib administration, he was admitted to our hospital due to HHS. His blood glucose level improved with insulin therapy after discontinuation of the ceritinib. He then received re-administration with a decreased ceritinib dose while maintaining the insulin treatment to control his blood glucose, but his HHS recurred. We discontinued the ceritinib for other side effects and noticed the HHS disappeared. Our findings suggest that ceritinib can cause HHS and that HHS may recur even after dose reductions.

Introduction

Various molecular-targeted anticancer drugs are under development. Some of these drugs have been reported to cause hyperglycemia due to their mechanisms of action [1].

Ceritinib is an inhibitor of anaplastic lymphoma kinase (ALK) and is indicated for ALK fusion gene-positive, unresectable, progressive, and recurrent non-small cell lung cancer (NSCLC). ALK inhibitors cause immediate tolerance, and ceritinib has been effective in patients with lung cancer who are resistant or intolerant to crizotinib (another ALK inhibitor) [2]. 3–5% of all lung cancer patients have NSCLC and ALK fusion gene positive [3]. Certinib is one of the options for those patients. The adverse effects of ceritinib include hyperglycemia [4], and this symptom was noted at a high frequency in 49% of patients in a phase II study [5]. However, information on the hyperglycemia severity and on the occurrence of hyperglycemic emergencies is limited. Here, we report the case of a patient with a hyperglycemic hyperosmolar state (HHS) that recurred after the re-administration of dose-reduced ceritinib.

Case presentation

A 78-year-old man presented with shortness of breath and a history of mitral regurgitation. The respiratory physician in charge discovered pleural effusion, and based on further evaluation, he was diagnosed with lung adenocarcinoma of the right middle lobe (T2aN3M1a; stage IV). The patient received chemotherapy for advanced NSCLC.

He was also being treated for type 2 diabetes since the age of 68 years and received an oral hypoglycemic agent (alogliptin, 25 mg) daily. The patient was monitored every month under the supervision of a respiratory physician. Before the onset of HHS, HbA1c was < 6% and was well managed. Even after ALK administration, HbA1c remained between 6 and 7% without sharp deterioration. The last HbA1c level examined 2 months before hospitalization was 6.8%, and random plasma glucose level was 227 mg/dL.

The patient was receiving chemotherapy for advanced NSCLC. Six months before the HHS onset, he had received carboplatin (400 mg), pemetrexed (900 mg), and bevacizumab (500 mg) as the first-line treatment. After the confirmation of an ALK-positive NSCLC, he had been started on crizotinib (500 mg/day, daily) and alectinib (600 mg/day, daily). However, the tumor-suppressing effects were poor. Therefore, ceritinib administration had been initiated (750 mg/day, daily).

The patient experienced reduced appetite after 16 days of ceritinib administration. After 28 days, he experienced extreme thirst and fatigue and was unable to eat; therefore, he visited the clinic. On physical examination, we found no abnormal body findings except for mild clarification and dryness of the skin. Table 1 presents the patient’s laboratory findings at the time. We found hyperglycemia, hyperosmolarity, and absence of metabolic acidosis or ketonuria. Thus, we diagnosed him as having HHS. He initially received isotonic saline and a continuous intravenous insulin infusion. His plasma glucose level and overall condition improved in a single day. After restarting oral food intake, the intravenous insulin infusion was changed to a basal–bolus subcutaneous insulin infusion. At discharge, he received 8 units of insulin glargine and 5 mg of linagliptin. His fasting plasma glucose level was maintained at approximately 120 mg/dL. His serum C-peptide level was 1.27 ng/mL (fasting blood glucose 147 mg/dL), and the urine C-peptide levels were 27.6 and 37.0 μg/day. A clinical response to ceritinib against the advanced NSCLC was recognized, and the agent was resumed at a reduced dose of 600 mg/day according to the manufacturer’s important safety information for ceritinib. We discharged him from the hospital on the 17th day of hospitalization (45 days after the start of ceritinib).

Table 1.

Laboratory data on admission

Variable		Reference range	Variable		Reference range
WBC	10,200 μIU/ml	0.4–4.7	Urinary ketone	–
Hb	13.0 ng/dl	1.0–1.8	pH	7.490	7.35–7.45
Plt	398,000/μl		pCO2	37.8 mmHg	37.0–44.0
BUN/creatinine	43/1.84 mg/dl	0.31–1.1	pO2	86.4 mmHg	80–100
Amylase	18 IU/l	37–125	HCO3−	28.5 mEq/l	22–26
Lipase	21 IU/l	11–53	Anion gap	12.5 mEq/l	10–14
Na	134 mEq/l	135–147	Serum C-peptide	1.27 ng/ml	0.8–2.3
K	5.5 mEq/l	3.3–4.8	Plasma Osmolarty	335 mOsm/l
Cl	93 mEq/l	98–108
Glucose	851 mg/dl
HbA1c	10.7%	4.6–6.2

HCO₃⁻: bicarbonate ion

However, 69 days after the start of ceritinib administration, his food intake was again reduced, and the patient visited the clinic again for a periodical consultation. His plasma glucose level was 756 mg/dL, and we found hyperosmolarity without ketonuria or metabolic acidosis (similar to the previous episode). Thus, we diagnosed him as presenting an HHS recurrence and admitted him to the hospital. Before this hospitalization, the patient denied ingesting sweetened beverages, and his insulin pharmacotherapy had been continual. He initially received isotonic saline and a continuous intravenous insulin infusion. At discharge, he received 8 units of insulin glargine and 5 mg of linagliptin (the same treatment as the one during the previous hospitalization). Ceritinib was discontinued because of elevated liver enzymes, and the HHS did not recur.

The patient had mild renal dysfunction. Before ceritinib administration, it was eGFR 66.3 ml/min/1.73 m², Cr 0.85 mg/dl, K 4.0 mEq/l. At the time of admission, eGFR was declined due to HHS, but it improved after treatment. At the time of the discharge, eGFR was 68.1 ml/min/1.73 m², Cr 0.83 mg/dl, K 4.0 mEq/l.

Discussion

We believe our case highlights two important findings. First, ceritinib can cause HHS. Second, HHS may recur after re-administration of dose-reduced ceritinib (following the important safety information guidelines).

ALK inhibitors exert anticancer effects by inducing apoptosis through the suppression of phosphorylation of downstream signaling components [1]. Ceritinib also inhibits the signals mediated by the insulin-like growth factor 1 (IGF-1) receptor [4], a tumor-enhancing factor. IGF-1 and insulin have a common receptor and intracellular transmitter; with the inhibition of the IGF-1 signal, the signal transduction from the insulin receptor and the insulin action are both inhibited, leading to hyperglycemia [6, 7]. At clinically relevant concentrations, ceritinib inhibits not only ALK and IGF-1 receptors but also the insulin receptor [8]. In addition, although crizotinib is ineffective against brain metastases, it has been effective in such cases owing to its ability to penetrate the blood–brain barrier [9]. The insulin receptors in the brain also contribute to the peripheral insulin action [10], and if these are inhibited, hyperglycemia may be promoted. Thus, ceritinib is thought to elevate blood glucose levels by inhibiting the insulin receptor and the IGF-1 receptor kinase [11].

However, the frequency of hyperglycemia is not constant: A phase II study reported hyperglycemia cases [12], but a phase III study did not [13]. Patients with a history of diabetes or impaired glucose tolerance have not been analyzed in this regard to date. The frequency of side effect reports has increased. According to the revised attachment, it was initially 2.3%, but is now reported to be 2.9%. Some reports of hyperglycemia due to ceritinib have been reported [14, 15]. The frequency of worsening glycemic control in patients with diabetes mellitus due to the administration of ceritinib has not been clarified. A study that analyzed the relationship between ALK inhibitors and hyperglycemia or diabetes mellitus in March 2019 [14] showed that the odds ratio for hyperglycemia-associated side effects was significantly high after the administration of ceritinib. Insulin is frequently used in hyperglycemic cases, and the side effects due to hyperglycemia are likely to occur in patients with decreased insulin secretion [14, 15]. Although a previous report also included a history of steroid use, our patient had no history of steroid use, and no other factors increasing the blood sugar levels were evident.

In cases of hyperglycemia after administration, ceritinib should be discontinued until the blood glucose level is controlled and subsequently resumed after reducing the dose by 150 mg [4]. Our patient continued insulin therapy and achieved good glycemic control. However, HHS recurred despite the re-administration of ceritinib at a reduced dose according to the safety information guidelines. Thus, HHS remains a possibility even if appropriate diabetes treatment is provided at the time of weight loss and good blood glucose control is maintained. Monitoring patients for hyperglycemia is important even after restarting ceritinib administration at reduced doses.

In another report [15], the onset of hyperglycemia was 2 weeks after ceritinib administration, but in our patient, it was 4 weeks later, and the recurrence became apparent 5 weeks after the re-administration. In our patient, the appearance of nonspecific hyperglycemic symptoms such as decreased appetite and gastrointestinal symptoms occurred after 2 weeks. Insulin requirements returned to normal 5 or 6 weeks after the last administration. The onset of hyperglycemia may vary from person to person, and attention to worsening hyperglycemia may be required every 2–6 weeks after ceritinib administration.

Ceritinib was initially approved under the dosage regimen of 750 mg orally once daily on an empty stomach, but many gastrointestinal toxicities, such as nausea, vomiting, and diarrhea, were observed. Overseas Phase I clinical trial (Study A2112) suggested that 450 mg once-daily administration was similar in exposure dose and efficacy and a tendency to reduce gastrointestinal toxicity. Therefore, in February 2019, the dosage and administration were changed. This case is the case before the change. It remains unclear whether the occurrence of side effects is dose dependent.

Elderly people easily cause dehydration due to conditions such as anorexia, vomiting, and diarrhea and the physiological compensation function of sodium ion may not function sufficiently; therefore, HHS is likely to occur. Cerinitib has a high frequency of anorexia as a gastrointestinal side effect. In this case, anorexia was exhibited immediately before the onset of HHS, but it is difficult to judge whether this symptom was an HHS-inducing factor or the initial symptom of HHS because both possibilities are considered. It should be noted that in cases of anorexia during the use of ALK inhibitors, not only frequent gastrointestinal side effects but also hyperglycemic emergencies need to be identified.

It is possible that this pathological condition was responsible for not only the increase in blood sugar level but also HHS. As described previously, it has been suggested that the inhibition of insulin receptor signaling by ceritinib reduces insulin action and causes hyperglycemia. In addition, it has been confirmed that ceritinib crosses the blood–brain barrier, and by acting on the insulin receptor in the brain, it may contribute to decrease in insulin action in the periphery and promote hyperglycemia. It is considered that HHS was developed due to the presence of conditions causing dehydration such as anorexia and functional decline of the thirst center due to aging in the relative insulin deficiency state reached in such a process. In this case, it was confirmed by post-hospital urinalysis that insulin secretion was not depleted, insulin treatment was also performed at the time of recurrence, and minimum amount of insulin was supplemented. Therefore, the formation of ketone bodies is unlikely to occur but it is possible that HHS occurred due to the presence of factors that promote dehydration. In addition, because the mechanism underlying ceritinib-associated hyperglycemia is impaired insulin action, even if insulin is supplemented, there is a possibility of causing marked hyperglycemia.

DPP-4 inhibitors, except saxagliptin, are not metabolized by a single isoform, and they do not interfere with the CYP system. We think that our patient had no drug interaction effects [16].

There are many common events between the signals of cell proliferation and glucose metabolism. Tyrosine kinase inhibitors may affect both cell proliferation and glucose metabolism.

The number of hyperglycemic emergency cases associated with ceritinib may increase as more patients receive ceritinib in the future. HHS should be considered as a serious adverse event of ceritinib administration.

New anticancer drug mechanisms have been elucidated. With regard to adverse events, close attention has been given mainly to the heart, lungs, liver, and skin, whereas limited attention has been given to impaired glucose metabolism. Traditionally, glycemic control in cancer chemotherapy involved mainly the prevention or treatment of hyperglycemia associated with steroid use. However, type 1 diabetes caused by PD-1 antibody can result in severe adverse events with the onset of diabetic ketoacidosis [17, 18]. Hyperglycemia may occur as a serious adverse event of new molecular-targeted drugs, such as IGF-1 receptor inhibitors, and PI3K inhibitors [4]. We think that the association between cancer chemotherapy and diabetes is ever increasing and may be referred to as onco-diabetology. Physicians who administer anticancer drugs should be aware of the possibility that these drugs cause hyperglycemic emergencies as adverse events. Also, educating patients about hyperglycemia may promote early treatment of this adverse event.

Compliance with ethical standards

Conflict of interest

Yuka Miyoshi, Osamu Ogawa, Ai Nishida, and Masahiro Masuzawa declare having no conflict of interest.

Informed consent

We obtained an informed consent or a substitute for it from the patient for being included in the study. We also obtained an additional informed consent from the patient for any identifying information included in this article.