Neutropenia as a Possible Cause of Rapalog-Induced Apthous Ulcers

I’m not aware of any studies specifically showing that apthous ulcers from rapalog use are the result of neutropenia, but it seems like a pretty strong hypothesis.

Rapalogs cause a decrease in neutrophils (I assume this is a result of a more generalized decrease in cell proliferation), and can cause neutropenia. Canker sores (apthous ulcers) commonly result from other causes of neutropenia:

A Case Report on Recurrent Oral Ulcers Associated with Cyclic Neutropenia

And there is some evidence linking rapalog-induced apthous ulcers to neutropenia:

A higher proportion of [mTOR inhibitor-associated stomatitis (mIAS)] patients than non-MIAS patients were neutropenic (19% vs 4%) and leukopenic (28% vs 17%), but myelosuppression was not a universal finding and was not associated with an increased incidence of infection or sepsis (Table 1). The incidence of fatigue and weight loss was similar in mIAS patients and non-mIAS patients. … Nonetheless, the possibility that neutropenia contributes to the etiology of mIAS cannot be disregarded given the similarity between the clinical appearance of mIAS and that of oral lesions observed in neutropenic patients.

mTOR inhibitor-associated stomatitis (mIAS) in three patients with cancer treated with everolimus
a typical [recurrent aphthous stomatitis (RAS)] lesion would be expected to manifest as a deep ulcer not surrounded by an erythematous halo, unlike the cases presented herein. In two of our patients for whom a CBC was available, there was bone marrow toxicity that may exist in mIAS, but no neutropenia. It should be noted that neutropenia does not exclude a diagnosis of mIAS, as the disease has been reported in patients with neutropenia.

A 45-year-old gentleman with IgA nephropathy as primary kidney disease had undergone cadaver donor renal transplantation in the year 2003. … He was initiated on sirolimus (6 mg on the first day followed by 2 mg/day as mainte­nance dose) in place of cyclosporine. Within a month after this, the patient presented with a painful confluent aphthous ulcers, on the tongue and lower lip … Everolimus was introduced in place of sirolimus at a dose of 0.75 mg twice a day. Two weeks following this, the aphthous ulcers disappeared [Figure 2]. The serum creatinine levels declined once the dehydration was corrected with intravenous fluids.
Initial studies suggested that infection with the herpes simplex virus, cytomegalovirus, and epstein-barr virus, as well as pneumocystis carinii occurred at a greater frequency among sirolimus-treated renal transplant recipients. Multicenter phase III trials revealed aphthous mucosal ulcers to occur more frequently, particularly among patients receiving sirolimus in a dose of 5 mg/day than those receiving 2 mg/day or placebo, in the Global (p= 0.002) but not the U.S. trial. [1] Aphthous stomatitis associated with sirolimus was reported in 9% of 150 psoriatic patients who received sirolimus. [2]
Sirolimus-induced Aphthous Ulcers which Disappeared with Conversion to Everolimus Ram R, Swarnalatha G, Neela P, Dakshinamurty KV - Saudi J Kidney Dis Transpl

In a study of “Seventeen patients, from a study cohort of 967, who were treated with sirolimus as prophylaxis for GVHD after allogeneic HSCT … [and] developed oral ulcers”, only 2 of the 17 had absolute neutrophil counts <1000, but that’s very severe neutropenia; it would be more useful to see patients with 1000-2000, and to see a correlation.
Mammalian Target of Rapamycin InhibitoreAssociated Stomatitis in Hematopoietic Stem Cell Transplantation Patients

A Google preview of this paper also looks informative, though I don’t have access (and would appreciate a copy from anyone who does).

Unfortunately, all the Mannick trials excluded anyone with absolute neutrophil counts (ANC) <2000 at baseline for this reason, with the result that her trials understate the occurrence of these if everolimus (or other rapalogs) were taken by unscreened individuals in the general aging population. The PEARL trial and Dr. Bradley Stanfield’s RAISE trial of rapamycin and exercise for muscle also exclude anyone with ANC <2000, which will lead to the the same unfortunate void in the evidence.

The obvious implication is to check your ANC before going on a rapalog, and keep checking thereafter. This is a good idea anyway, since a very low ANC might make you susceptible to dangerous infections.


Interesting… more on neutropenia:


I had meant to include this: it’s a more action-oriented guide to neutropenia from the Cleveland Clinic

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