mTOR Inhibitor-associated Stomatitis Research Articles

Dexamethasone to prevent everolimus-induced stomatitis (Alliance MIST Trial: A221701)

mTOR inhibitors such as everolimus may cause oral stomatitis, often a dose-limiting toxicity. Prior clinical research has suggested that a dexamethasone mouth rinse might help prevent and/or treat this. Alliance A221701 was a randomized phase III trial of patients initiating 10 mg daily oral everolimus that compared dexamethasone mouthwash taken preventively (initial dexamethasone group) versus therapeutically (initial placebo group) to assess two coprimary endpoints: the incidence of mTOR inhibitor-associated stomatitis (mIAS), and the area under the curve (AUC) of mIAS-associated pain over an 8-week treatment period. A Fisher's exact test was used to compare the incidences while a Wilcoxon rank-sum test was used to compare the AUCs. In addition, we performed an exploratory analysis of the association of everolimus trough concentrations and toxicity using a Mann-Whitney U test. Due to slow accrual, this study closed after 39 patients were randomized (19 to upfront placebo and 20 to upfront dexamethasone). There were no significant differences between groups seen in either of the coprimary endpoints; furthermore, we found no association between whole blood everolimus trough concentrations and toxicity. Although limited by poor enrollment, the results of this study do not suggest that prophylactic dexamethasone mouthwash is superior to therapeutic dexamethasone mouthwash (initiated at the first sign of mouth pain) for reducing the incidence or severity of mIAS from everolimus.

Adding Azathioprine and Hydroxyurea Preconditioning to Alemtuzumab/TBI May Improve Donor Chimerism in Matched Sibling Donor Allogeneic Stem Cell Transplantation in Adult Sickle Cell Patients

Introduction Sickle cell disease (SCD) is a severe, inherited hemoglobinopathy, characterized by hemolysis, vaso-occlusive crisis (VOC) and progressive organ damage, resulting in poor quality of life and reduced life expectancy. Improvements in supportive care, use of (exchange) blood transfusions and hydroxyurea have resulted in better survival in SCD children. Nevertheless, SCD related organ damage continues during adult life, resulting in increased morbidity and mortality. Allogeneic stem cell transplantation is currently the only curative treatment option for SCD. In adults, myeloablative conditioning is associated with significant toxicity, primarily due to cumulative organ damage. Matched sibling donor (MSD) transplantation with non-myeloablative conditioning (alemtuzumab + 3 Gy total body irradiation (TBI)) using peripheral blood stem cells has shown promising results in adult SCD patients. In patients treated with this regimen the SCD phenotype resolved with only mild transplantation-related complications, but no reports of graft-versus-host disease (GvHD). However, a large part of these patients did not reach complete donor chimerism and graft failure rates of 8-13% have been reported with this regimen (Hsieh et al. JAMA, 2014; Saraf et al. Biol Blood Marrow Transplant, 2016). Adding azathioprine and hydroxyurea as preconditioning to the alemtuzumab/TBI regimen might improve donor chimerism and reduce risk of graft failure. In this study we prospectively investigate the effects of azathioprine/hydroxyurea preconditioning prior to alemtuzumab/TBI conditioning on donor chimerism and graft failure in patients receiving MSD allogeneic stem cell transplantation for SCD. Methods Adult SCD patients with complications refractory to standard care who had an HLA-identical sibling donor were eligible for this treatment. After 3 months of azathioprine 150mg qd and hydroxyurea 25mg/kg qd, erythrocyte exchange transfusion was performed on day -10, aiming for HbS <30%. Conditioning with alemtuzumab and TBI was started on day -7, as described by Hsieh et al (N Engl J Med, 2009). GvHD prophylaxis consisted of sirolimus. Data regarding SCD phenotype, donor chimerism and transplantation-related complications were collected prospectively. Results Eight patients (6 HbSS, 2 HbS-β+-thalassemia; median age 29 (range 21 - 49) years; 3 males) have been transplanted as of March 2018. All but one patient reached 100 % donor myeloid chimerism at 1 month. Myeloid chimerism remained stable in those who had reached full donor chimerism at one month (Figure 1A). One patient had 69% donor myeloid chimerism at 1 month, which increased gradually to 90 % at 9 months. Median T-cell donor chimerism at 3 months was 37% (range: 23 - 79%; n=6), increasing further during follow-up (Figure 1B). The percentages of donor myeloid and T-cell chimerism are higher than previously reported with alemtuzumab/TBI only (Hsieh et al. JAMA, 2014). All patients had a corrected SCD phenotype with mostly normalized hemoglobin levels at 3 months (from median 9,5 (IQR 7.8 - 10.7) g/dL at baseline to 12.4 (11.6 - 13.5) g/dL at 3 months, increasing further thereafter. Sirolimus tapering was started at 12 months in the first transplanted patient and stopped without affecting donor chimerism. There were no reports of SCD-related complications. One patient developed acute grade III intestinal GvHD, despite appropriate trough levels of sirolimus, though responded well to high dose steroids. Other treatment-related complications were mTOR inhibitor-associated stomatitis (n=5) responding well to local steroids, arthralgia that was moderately severe in 2 patients and progression of preexistent chronic kidney injury in one patient, which partially recovered after switching sirolimus to mycophenolate mofetil. Conclusion Azathioprine/hydroxyurea preconditioning prior to alemtuzumab/TBI conditioning is well tolerated and may result in improved (higher) donor chimerism after non-myeloablatieve MSD transplantation in SCD patients. Importantly, one patient developed acute GvHD. As (acute) GvHD following alemtuzumab/TBI conditioning has not been reported previously, a relation with the preconditioning (azathioprine) cannot be excluded. Longer term results of larger cohorts are needed to determine the place of azathioprine/hydroxyurea preconditioning in non-myeloablative MSD transplantation for SCD. Disclosures Nur: Novartis Pharmaceuticals: Consultancy. Zeerleder:Jazz Pharma: Speakers Bureau; Sanofi/Genzyme: Speakers Bureau; Alexion: Speakers Bureau.

Breast cancer patients have increased risk of developing mTOR inhibitor-associated stomatitis.

A total of 115 patients who used everolimus were evaluated. The mean age was 57 (±13.3) years old, and 87 patients were women (75.6%). mTOR inhibitor-associated stomatitis (mIAS) was observed in 36 patients (31.3%). The lesions ranged from 0.5cm to 1.5cm, and the tongue was the main site affected. In addition, 21 patients (58.3%) required a dose reduction of everolimus due to mIAS. Patients who had breast cancer presented 2.29-fold higher risk for developing mIAS when compared to patients with kidney or neuroendocrine tumors. This study emphasizes the high prevalence of mIAS in patients using everolimus, in particular, in patients with breast cancer.

Prevention and treatment options for mTOR inhibitor-associated stomatitis

Prevention and treatment options for mTOR inhibitor-associated stomatitis

Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors.

Development of biological targeted therapies and immune checkpoint inhibitors has redefined the treatment for many cancers; however, the increasing use of new protocols has led to physicians observing a new spectrum of toxicities. To date, oral adverse events induced by these new anticancer therapies have been mainly reported using nonspecific terminology ("stomatitis," "mucosal inflammation," "mucositis") and remain poorly characterized, with the exception of mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis. Oral toxicities of targeted therapies often display very characteristic features which clearly differ from classic oral injuries observed with cytotoxic chemotherapy and/or radiotherapy. In addition, they frequently affect more than 20% of treated patients and can lead to a significant morbidity or permanent treatment discontinuation. Oral mucosal toxicities described in this review include mTOR inhibitor-associated stomatitis (mIAS); stomatitis, benign migratory glossitis, and osteonecrosis of the jaw associated with multi-targeted kinase inhibitors of the VEGF and PDGF receptors; mucositis induced by EGFR inhibitors (in monotherapy or in combination with head and neck radiotherapy and/or chemotherapy); hyperkeratotic lesions with BRAF inhibitors; pigmentary changes and lichenoid reactions secondary to imatinib; and more recent data on the "Osler-Weber-Rendu-like syndrome" described with the antibody-drug conjugate, TDM-1. Finally, we provide, to our knowledge, the first available structured data on oral toxicities induced by the new recently FDA- and EMA-approved monoclonal antibodies targeting PD-1. Clinical management of these targeted therapy-related oral changes is also discussed.

On the pathogenesis of mTOR inhibitor-associated stomatitis (mIAS)-studies using an organotypic model of the oral mucosa.

mTOR inhibitor treatment of solid cancers is associated with mTOR inhibitor-associated stomatitis (mIAS) a common, significant, dose-limiting toxicity, with aphthous-like lesions. Our objective was to assess the utility of a new organotypic model in defining mIAS' pathogenesis. The effect of everolimus on organotypic human oral mucosa was studied. Sterile specimens were assessed 24 and 48h after exposure to varying concentrations of everolimus. Morphologic changes and measures of apoptosis, proliferation, and levels of six Th1 and Th2 cytokines were studied. Following a 24-h incubation, concentrations of 500ngml-1 of everolimus resulted in histological changes consistent with epithelial injury, disorganization and pre- or early apoptosis, increased TUNEL-positive staining (P<0.05) and reduced PCNA-positive staining cells (P<0.001) and increased levels of IL-6 (P<0.0001), IL-8 (P<0.01), and IFN-γ (P<0.09). Everolimus elicited epithelial damage manifest by morphologic changes, increased apoptosis, and decreased proliferation with concurrent release of keratinocyte-derived pro-inflammatory cytokines in the absence of bacteria. The extent of the effect was concentration and time dependent. These results suggest that mIAS is likely initiated by direct epithelial injury, independent of the microbiome. Keratinocyte cytokine release could likely play a role in accelerating an inflammatory infiltrate.

Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice.

In recent years oral mucosal injury has been increasingly recognized as an important toxicity associated with mammalian target of rapamycin (mTOR) inhibitors, including in patients with breast cancer who are receiving everolimus. This review addresses the state‐of‐the‐science regarding mTOR inhibitor‐associated stomatitis (mIAS), and delineates its clinical characteristics and management. Given the clinically impactful pain associated with mIAS, this review also specifically highlights new research focusing on the study of the molecular basis of pain. The incidence of mIAS varies widely (2–78%). As reported across multiple mTOR inhibitor clinical trials, grade 3/4 toxicity occurs in up to 9% of patients. Managing mTOR‐associated oral lesions with topical oral, intralesional, and/or systemic steroids can be beneficial, in contrast to the lack of evidence supporting steroid treatment of oral mucositis caused by high‐dose chemotherapy or radiation. However, steroid management is not uniformly efficacious in all patients receiving mTOR inhibitors. Furthermore, technology does not presently exist to permit clinicians to predict a priori which of their patients will develop these lesions. There thus remains a strategic need to define the pathobiology of mIAS, the molecular basis of pain, and risk prediction relative to development of the clinical lesion. This knowledge could lead to novel future interventions designed to more effectively prevent mIAS and improve pain management if clinically significant mIAS lesions develop.

Current Management of mTOR Inhibitor-Associated Stomatitis

mTOR inhibitor-associated stomatitis (mIAS) is an adverse event associated with mTOR inhibitor treatment for advanced cancers. mIAS tends to occur within 2 weeks of treatment start and resolve within weeks of symptom onset. mIAS is usually mild in severity and often self-limiting. Nevertheless, inadequately controlled mIAS can negatively affect patient function and treatment adherence. This review summarizes efficacy and mIAS safety data of mTOR inhibitors, and discusses prevention and treatment of mIAS. Patient cases are used to illustrate important practice points. Although mIAS has been recognized as a cancer treatment-related adverse event only in the last decade, several clinical studies are ongoing. This raises the expectation that management of mIAS in the future will be guided by strong evidence.

Mammalian Target of Rapamycin Inhibitor-Associated Stomatitis

With the recent introduction of inhibitors of mammalian target of rapamycin (mTOR) in oncology, distinct cutaneous and oral adverse events have been identified. In fact, stomatitis and rash are documented as the most frequent and potentially dose-limiting side effects. Clinically, mTOR inhibitor-associated stomatitis (mIAS) more closely resembles aphthous stomatitis than oral mucositis due to conventional anticancer therapies. While most cases of mIAS are mild to moderate and self-limiting, more severe and persistent mIAS can become a dose-limiting toxicity. Small ulcerations may cause significant pain and mucosal sensitivity may occur in the absence of clinical changes. Use of clinical assessment tools that are primarily driven by ulceration size may underestimate mIAS, and assessment should include patient-reported outcomes. This article provides an up-to-date review of the clinical presentation, terminology, pathogenesis, assessment and management of mIAS and other mTOR inhibitor-associated oral adverse events. In addition, areas of future research are considered.

Managing Stomatitis in Patients Treated With Mammalian Target of Rapamycin Inhibitors

Mammalian target of rapamycin (mTOR) inhibitors are a class of targeted cancer therapeutic agents with clinical benefit for multiple tumor types. Oral ulcerations are a common side effect of mTOR inhibitors; however, the clinical findings resemble aphthous stomatitis rather than the mucositis seen with chemotherapy. Consequently, the appearance of aphthous-like oral ulcerations has been referred to as mTOR inhibitor-associated stomatitis (mIAS). The severity of mIAS can be minimized by following common preventive steps and initiating treatment at the first sign of mouth discomfort, thereby reducing the likelihood of treatment discontinuation. mIAS can be managed through prophylactic measures, such as patient education in oral hygiene and avoidance of triggers. Patients who develop mIAS may be treated topically using rinses or other local therapies, including corticosteroids. In severe cases, dose modifications may be required. Oncology nurses have an important role in the management of patients with cancer and are well positioned to offer strategies for minimizing the occurrence and impact of mIAS.

Clinical presentation and management of mTOR inhibitor-associated stomatitis

Anti-cancer agents that inhibit the mTOR pathway are associated with a number of unique toxicities, with one of the most significant and potentially dose-limiting being stomatitis. The objective of this study was to report the clinical features and management outcomes of a series of cancer patients who developed painful mTOR inhibitor-associated stomatitis (mIAS). Seventeen cancer patients developed mIAS while being treated with everolimus- or ridaforolimus-containing protocols at the Dana-Farber Cancer Institute and were referred to the oral medicine clinic for evaluation and management. Clinical characteristics, toxicity management, and outcomes were summarized. In addition, the frequency and rationale for dose reductions and therapy discontinuation were assessed. The median duration of mTOR inhibitor therapy was 80 days (range 9-187 days). The median time to development of mouth ulcers was 10 days (range 4-25 days). Five patients required protocol-directed dose reductions due to grades 2 and 3 stomatitis and one patient discontinued cancer treatment due to mouth ulcers. Clinical improvement and pain relief was reported in 86.6% of patients following topical, intralesional, or systemic corticosteroid therapy, with side effects limited to secondary candidiasis (n=2). Mouth ulcers are a common and potentially dose limiting toxicity associated with the use of mTOR inhibitors in cancer treatment. This case series demonstrates that local and systemic corticosteroid therapy is an effective approach to managing patients with symptomatic mIAS. Prospective studies are necessary to evaluate the effectiveness of treatment and prevention strategies with the ultimate goal of improving overall cancer treatment outcomes.

Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients

Mammalian target of rapamycin (mTOR) inhibitors may have efficacy as an intervention for advanced malignancies. Oral ulceration (OU), reported as mucositis, has been a dose-limiting toxicity for this new class of agents. An analysis of the appearance, course, and toxicity associations of mTOR inhibitor-associated stomatitis (mIAS) demonstrated that the condition is distinct from conventional mucositis (CM) and more closely resembles aphthous stomatitis. Safety data from 78 solid tumor patients enrolled in 2 Phase 1, multicenter trials of the mTOR inhibitor deforolimus (AP23573, MK-8669) were evaluated. Adverse events (AEs) based on National Cancer Institute Common Toxicity Criteria for National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0) criteria were coded, consolidated, and stratified according to the presence or absence and duration of concordant OU. The relation between OU and other AEs was analyzed. Treatment-emergent AEs were reported in 91% of 78 study participants. OUs were reported in 66%, appeared within 5 days of deforolimus administration, and were discrete, ovoid, superficial, well demarcated, and surrounded by an erythematous halo. Their clinical appearance and distribution were similar to that of aphthous stomatitis but inconsistent with CM. Patients with OU were more likely to have nonspecific rashes and acneiform dermatitis but not gastrointestinal AEs. OU associated with mTOR inhibitor therapy differed from CM. Lesions more closely resembled those of aphthous stomatitis. The lack of other gastrointestinal involvement but the presence of a higher incidence of concomitant cutaneous AEs provided additional evidence to suggest a distinction between mIAS and CM. Treatment strategies for aphthous stomatitis may be a rational approach for the prevention and control of mIAS.