Midostaurin-Associated acute pancreatitis

Introduction

The multikinase inhibitor midostaurin is the first targeted therapy to improve overall survival in patients with acute myeloid leukemia and the FLT3 mutation. In the RATIFY study, Midostaurin improved survival compared with standard chemotherapy as an upfront treatment for high-risk patients with AML and FLT3 mutations. ¹ At a median follow-up of 57 months, midostaurin reduced mortality by 23% more than standard chemotherapy. Midostaurin increased overall survival, prevented the onset of symptoms and improved quality of life. ¹ Nausea, vomiting, abdominal pain, mucositis, diarrhea, lymphopenia, leukopenia, anemia, hyperglycemia, hypernatremia, elevated liver enzymes, headache and dizziness, peripheral edema, chills are common advers effects of the drug. Although many gastrointestinal side effects have been reported because of midostaurin there is no data on pancreatitis. In this study, we report a case of midostaurin-associated acute pancreatitis.

Case presentation

A 62-year-old male patient with history of type-2 diabetes mellitus, hypertension, hyperlipidemia and AML came to the emergency department with complaints of abdominal pain, nausea and loss of apetite patient had no history of pancreatitis. The abdominal pain had started 2 days ago, did not radiate to the back, and intensified after meals. Although he had intermittent nausea, he had never vomited. On physical examination, fever was 36.6 degrees, arterial blood pressure 135/80 mmHg, pulse 75/min, respiratory rate 16/min, abdomen slightly distended, epigastric tenderness, no defense, no rebound, Murphy's sign was negative. During auscultation, both lungs participate equally in respiration, no rales or rhonchi. On CVS examination, S1+ S2 + and cardiac rythm were normal, no additional sound or murmur, peripheral pulses were felt clearly in 4 extremities. The patient was diagnosed with AML 6 months ago and midostaurin was added to his treatment to be taken 2 × 50 mg daily upon the positive result of FLT3 gene in genetic analysis. The patients laboratory results on admission are shown in Table 1. Contrast-enhanced upper abdominal computed tomography of the patient revealed no additional pathology except for a slightly voluminous pancreas (Picture 1). Abdominal ultrasound performed on admission showed normal gallbladder and biliary tract. MRCP imaging was found to be normal. The patient with abdominal pain, who has more than 3-fold increased in amylase-lipase values and edema around the pancreas on abdominal imaging was evaluated as acute edematous pancreatitis according to the Revised Atlanta Classification. Acute pancreatitis severity scores were calculated as APACHE II: 8, Ranson-0: 2, Ranson-48: 0 and BISAP: 1. According to these severity scoring systems, our patient was evaluated as mild pancreatitis. The patient had been taking nebivolol, atorvastatin, insulin glargine and insulin aspart at the same doses for 2 years. His blood pressure was under control and also his blood glucose and cholesterol levels were within the normal range. In our patient, midostaurin-related acute pancreatitis was diagnosed after other causes that could cause acute pancreatitis were excluded. Naranjo score was 5 for the drug adverse reaction. ² Midostaurin treatment and patient's oral feeding was stopped.hydration was started. Proton pump inhibitor, analgesics for pain and anti-emetics were added to the treatment in case of necessity.Complete blood count and biochemistry tests were examinated during hospitalization. On the 2nd day of hospitalization, the patient's diet was changed to the R1, as the patient had no abdominal pain, nausea and vomiting, and amylase-lipase values decreased.There was no intolerance. It was updated to the R2 the next day and the R3 in the evening. The patient did not develop abdominal pain and nausea. On the 4th day of hospitalization, the patient whose acute pancreatitis regressed was discharged with recommendations.

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Picture 1.

The CT image of the patient that showing an edematous pancreas and some fluid collections around the pancreas.

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Table 1.

Laboratory results of the patient at the time of admission.

Laboratory Parameters	Results
Hemoglobine (gr/dl)	12.4
Hematocrit (%)	35.8
Platelet (µl)	98000
White Bood Cell (µl)	4600
Glucose (gr/dl)	508
C-reactive protein (U/L)	50
Gama glutamyl transferase (U/L)	219
Alkaline phospathase (U/L)	36
Alanine aminotransferase (U/L)	95
Aspartate aminotransferase (U/L)	50
Lactate dehydrogenase (U/L)	191
Urea (mg/dl)	50
Creatinine (mg/dl)	0.88
Total Bilirubin (mg/dl)	0.66
Direct Bilirubin (mg/dl)	0.14
Calcium (mg/dl)	9
Sodium (mmol/l)	136
Potassium (mmol/l)	4.02
Amylase (U/L)	444
Lipase (U/L)	1078
Triglyceride (mg/dl)	226

Discussion

Drug-induced pancreatitis is less common compared to other causes of acute pancreatitis; the incidence ranges from between 0.1% to 2% of acute pancreatitis cases.^3,4 In the majority of cases, pancreatitis regresses within a few days after the drug is discontinued. All other causes must be ruled out in order to be able to show that a drug is associated with acute pancreatitis. Most of the published articles on this topic are in the form of a single case report. Drugs are divided into 4 main classes by Badalov et al. ⁵ according to their potential to cause acute pancreatitis. The principle of the classification is based on the number of case reports related to the condition: The time from the initiation of the drug to the development of acute pancreatitis (latent period), and the criteria for the development of pancreatitis after re-exposure to the drug. Class I drugs refer to drugs that show a recurrence of pancreatitis attack after re-exposure. Class I drugs are divided into two groups according to the exclusion of other causes of pancreatitis. In this system, class Ia refers to drugs for which exclusion is made, and class Ib refers to drugs for which exclusion cannot be made. Class II drugs are those in which the latent period is shown in 75% of at least four reported cases. Class III drugs are drugs that have reported at least two cases in which both the latent period cannot be demonstrated and pancreatitis cannot be demonstrated by re-exposure. Class IV drugs, on the other hand, refer to drugs in which a single case has been reported in which both the latent period cannot be demonstrated and pancreatitis cannot be demonstrated by re-exposure. Class 1 and class 2 are the groups with the highest potential to develop acute pancreatitis. Since the drug in our case is the first example in the literature in the light of the available information, it is not clear which class it falls into. ⁵ The most commonly accused drugs in the etiology of acute pancreatitis are thiazides, furosemide, sulfanomides, ACE inhibitors, tetracyclines, valproic acid, pentamidine, azathiopirine, 6-mercaptopurine, oral contraceptives, organophosphate insecticides, metronidazole, dapsone, isoniazid, mesalamine, erythromycin, NSAIDs, corticosteroids. ⁶ Possible mechanisms of the development of drug-induced pancreatitis include immunological reactions, direct toxic effect, accumulation of toxic metabolites, overstimulation of pancreatic acinar cells, ischemia, intravascular thrombosis, and an increase in the viscosity of pancreatic secretion. ⁷ The patients type2 diabetes and hyperlipidaemia may be risk factors for pancreatitis, but diseases were under control and also he had no history of pancreatitis. Given this, acute pancreatitis was thought to be related to midastaurn. Although midostaurin has many side effects on the gastrointestinal tract, there is no data in the literature on its relationship with acute pancreatitis.

Conclusion

In this case, midostaurin was added to AML-FLT3 treatment and the patient developed acute pancreatitis. After excluding other possible causes, we considered midostaurin as the usual suspect as the etiology of acute pancreatitis. Although oddi sphincter manometry should be performed for oddi sphincter dysfunction, which is another cause of acute pancreatitis, we did not perform oddi sphincter manometry because the patient had no previous history of acute pancreatitis.

Written consent was obtained from the patient.

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