Imatinib, cheese and migraines
Michael Woodfin , Laura Bickel & Michael Deininger
To cite this article: Michael Woodfin , Laura Bickel & Michael Deininger (2020): Imatinib, cheese and migraines, Leukemia & Lymphoma, DOI: 10.1080/10428194.2020.1839652
To link to this article: https://doi.org/10.1080/10428194.2020.1839652
Published online: 28 Oct 2020.
Submit your article to this journal
Article views: 3
View related articles View Crossmark data
Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ilal20
LEUKEMIA & LYMPHOMA
LETTER TO THE EDITOR
Imatinib, cheese and migraines
Michael Woodfina , Laura Bickelb,c and Michael Deiningerb,c
aUniversity of Washington School of Medicine, Seattle, WA, USA; bHuntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; cDivision of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, USA
ARTICLE HISTORY Received 6 August 2020; revised 24 September 2020; accepted 15 October 2020
Here we report a patient with maculopapular cutaneous mastocytosis who developed imatinib-induced cheese sensitivity manifest as migraine headaches. We discuss possible mechanisms of imatinib induced sensitivity to cheese.
Mastocytosis is characterized by a pathological increase and activation of mast cells in tissues and is sub- classified as cutaneous mastocytosis (CM) or systemic mastocytosis (SM) . CM encompasses a group of disor- ders characterized by accumulation of mast cells in the skin with an absence of systemic involvement, while sys- temic mastocytosis (SM) is characterized by infiltration of extracutaneous organs with abnormally shaped mast cells grouped in clusters. Maculopapular cutaneous mastocyto- sis (also called urticaria pigmentosa, UP) is the most com- mon form of cutaneous mastocytosis, usually presenting in childhood as fixed, itchy brown plaques .
A 24-year-old woman was referred to our clinic for management of UP. She reported numerous cutaneous symptoms, including pruritis, edema, and cosmetic con- cerns. She had been diagnosed with UP at the age of 3. Since that time, she had undergone various therapies including psoralen and UVA phototherapy and histamine receptor blockers (doxepin, diphenhydramine, and lorata- dine). Despite these treatments her skin lesions and symptoms continued to progress. Laboratory testing was normal, including serum tryptase which was in the nor- mal range at 8.4 ng/ml
Patients with cutaneous mastocytosis may have either a point mutation at position 816 in the activation loop of KIT that locks the kinase in an active conformation (most patients with systemic mastocytosis have KIT D816V), or they may have a mutation in the extracellular domain KIT (exon 8 or 9) [1,3]. Oncogenic exon 8/9 mutants retain a normal conformation of the catalytic site, but display increased affinity for KIT ligand (stem cell factor) or acti- vation of KIT in a ligand-independent manner . KIT activation is integral to numerous mast cell functions, including differentiation from precursors, maturation, sur- vival, chemotaxis, and potentiation of IgE-mediated acti- vation .
In our patient, screening for KIT mutations on a skin biopsy (UP-involved area) with capillary electrophoresis detected a three base pair shift in band size in KIT exon 8, consistent with an exon 8 mutation. Given her contin- ued severe symptoms and considerable psychological stress due to cosmetic concerns, a joint decision was taken to initiate imatinib, after careful discussion of potential adverse effects. In March 2014 she was started on imatinib 400 mg/day. Imatinib, a KIT inhibitor, is inef- fective in patients with a KIT D816V mutation, but has considerable activity in patients with exon 8/9 mutations . Typical adverse effects of imatinib include anemia, neutropenia, edema, nausea, diarrhea, and headache .
At a follow-up visit in August 2016 the patient noted
resolution of cutaneous symptoms but stated that she had been experiencing migraine headaches. The head- aches occurred almost daily, began with a prodrome of photosensitivity and nausea, and were followed by blurred vision and black spots in her visual field. During the migraine episodes she had difficulty functioning at work, but did not lose the ability to perform basic self- care activities such as eating and dressing. Darkness and rest provided some relief. A diagnosis of typical migraine was made. Sumatriptan improved symptoms, but was self-discontinued because of fatigue and nausea. Her medications were reviewed for known migraine triggers and drug interactions, with no significant findings. She reported analgesic use less than once monthly, making medication overuse (rebound) headache unlikely. To identify potential food triggers, an elimination diet was initiated. Elimination of cheese from her diet abrogated migraine attacks. She was unsure if a particular kind of cheese was to blame, but she noted that cheddar cheese, string cheese and pizza had triggered her headaches. She began avoiding all cheese except for occasional cream cheese, which does not trigger migraines. In March 2017, imatinib was held for one month to see whether UP would remain in remission. Suspecting that imatinib played a role in the induction of her migraines, the patient added cheese back to her diet. She experienced no migraines during this imatinib free period. In April
CONTACT Michael Deininger [email protected] University of Washington School of Medicine, Seattle, WA, USA
© 2020 Informa UK Limited, trading as Taylor & Francis Group
2 M. WOODFIN ET AL.
2017, her skin lesions returned, and she was restarted on imatinib, with improvement of UP and prompt recurrence of cheese-induced migraines. Reintroduction of a cheese- free diet eliminated migraines. She continues imatinib therapy with complete remission of UP.
Headaches are not uncommon in patients treated with imatinib. For instance, 37% of patients treated in the IRIS study of imatinib in newly diagnosed chronic myeloid leukemia reported headaches, the majority of which were grade 1 or 2 adverse events . We are not aware of any work that has tried to determine the eti- ology of headache in patients on imatinib therapy. Our case suggests that an imatinib-induced dietary trigger may be the cause of headache in some patients.
Dietary migraine triggers have been well documented; one study that examined the relationship between cheese and migraine found an incidence of 18% . Despite this, the mechanism by which diet triggers migraines in some patients is poorly understood.
In our patient, the relationship between imatinib ther- apy and cheese triggered migraine is demonstrated by the fact that she had no history of migraine. She then experienced cheese-triggered migraines after beginning therapy, which resolved during a brief imatinib free period, and then promptly returned after restarting ther- apy. The mechanism by which imatinib causes cheese triggered migraine in this patient remains unclear. However, biogenic amines found in cheese, such as tyr- amine, histamine, and serotonin, amongst others, have been implicated in cheese-associated migraines, and may play a role in our patient . Tyramine has been widely reported as a migraine trigger, but studies supporting tyramine effects have been criticized for methodological flaws and several other studies have failed to find a rela- tionship . Failure of tyramine to trigger migraine in these studies might be explained by the fact that tyram- ine alone was administered instead of combined with other biogenic amines, which may act synergistically to produce migraine. For example, tyramine is known to inhibit the breakdown of histamine , which in turn may trigger migraines .
Cheese is known to cause headache and hypertensive crisis in patients taking monoamine oxidase A (MAO-A) inhibitors. MAO-A inhibitors prevent the breakdown of the biogenic amine tyramine, potentiating its pressor effects . Imatinib is not an inhibitor of MAO-A, but it could interfere with the metabolism of biogenic amines through another mechanism. See supplement for discus- sion of cytochrome p450 enzymes and imatinib.
Imatinib has been shown to be a potent inhibitor of Human Organic Cation Transporter 1 (OCT1) . OCT1 is an in vitro transporter of tyramine, although studies have failed to find a relationship between OCT1 genotypes and tyramine metabolism . OCT-1 is also thought to be a key component in the hepatic elimination of sero- tonin . Serotonin has a complex role in migraine physiology with both pro-nociceptive and anti-
nociceptive effects . Finally, imatinib’s inhibition of OCT1 may have also played a role in this patient’s intolerance of sumatriptan, as OCT1 plays a major role in the hepatic breakdown of sumatriptan .
Migraine pathophysiology is complex and poorly understood, as is the mechanism by which certain foods trigger migraines. We propose several metabolic path- ways that may be involved in our patient, but further investigation into food triggered migraine is warranted to identify the exact mechanism. It is unclear whether all patients treated with imatinib can experience cheese induced migraine, or whether patients with mastocytosis are particularly vulnerable. Our case suggests that an elimination diet should be considered in all patients with imatinib-induced migraines.
No potential conflict of interest was reported by the author(s).
Michael Woodfin http://orcid.org/0000-0002-0820-3166
 Akin C. Molecular diagnosis of mast cell disorders: a paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology. Assoc Mol Pathol. 2006;8(4):412–419.
 Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and
classification of mastocytosis: a consensus proposal. Leuk Res. 2001;25(7):603–625.
 Reshetnyak AV, Opatowsky Y, Boggon TJ, et al. The strength
and cooperativity of kit ectodomain contacts determine nor- mal ligand-dependent stimulation or oncogenic activation in cancer. Mol Cell. 2015;57(1):191–201.
 Galli SJ, Tsai M, Wershil BK. The c-kit receptor, stem cell fac- tor, and mast cells: What each is teaching us about the others. Am Soc Investigat Pathol. 1993;142(4):965–974.
 Gotlib J, Gerds AT, Bose P, et al. Systemic mastocytosis, ver-
sion 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018;16(12):1500–1537.
 Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of
patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408–2417.
 Peatfield RC, Glover V, Littlewood JT, et al. The prevalence of
diet-induced migraine. Cephalalgia. 1984;4(3):179–183.
 Stratton JE, Hutkins RW, Taylor SL. Biogenic amines in cheese and other fermented foods: a review. Int Assoc Food Protect. 1991;54(6):460–470.
 Jansen SC, Van Dusseldorp M, Bottema KC, et al. Intolerance
to dietary biogenic amines: a review. Ann Allergy Asthma Immunol. 2003;91(3):233–241.
 Hui JY, Taylor SL. Inhibition of in vivo histamine metabolism
in rats by foodborne and pharmacologic inhibitors of diamine oxidase, histamine N-methyltransferase, and mono- amine oxidase. Toxicol Appl Pharmacol. 1985;81(2):241–249.
 Worm J, Falkenberg K, Olesen J. Histamine and migraine
revisited: mechanisms and possible drug targets. J Headache Pain. 2019;20(1):30.
IMATINIB, CHEESE AND MIGRAINES 3
 Boxberger KH, Hagenbuch B, Lampe JN. Common drugs inhibit human organic cation transporter 1 (oct1)-mediated neurotransmitter uptake. Drug Metab Dispos. 2014;42(6): 990–995.
 Rafehi M, Faltraco F, Matthaei J, et al. Highly variable pharmacokinetics of tyramine in humans and polymorphisms in OCT1, CYP2D6, and MAO-A. Front Pharmacol. 2019; 10(OCT):1297–1297.
 Kilinc E, Guerrero-Toro C, Zakharov A, et al. Serotonergic mechanisms of trigeminal meningeal nociception: implica- tions for migraine pain. Neuropharmacology. 2017;116: 160–173.
 Matthaei J, Kuron D, Faltraco F, et al. OCT1 mediates hepatic uptake of sumatriptan and loss-of-function OCT1 polymor- phisms affect sumatriptan pharmacokinetics. Clin Pharmacol Ther. 2016;99(6):633–641.