Correspondence

¹Epidemiology & Cancer Statistics Group, Department of Health Sciences, University of York, York, ²Haematological Malignancy Diagnostic Service, St James's University Hospital, ³Bioinfomatics Group, Institute of Molecular and Cellular Biology, University of Leeds, Leeds, ⁴Queen's Centre for Oncology and Haematology, Hull and East Yorkshire Hospitals, Cottingham, and ⁵Section of Experimental Haematology, University of Leeds, Leeds, UK.

E-mail: eve.roman@york.ac.uk

**Keywords:** gene-expression, prognostic factors, survival, epidemiology

First published online 8 November 2018
doi: 10.1111/bjh.15619

**Supporting Information**

Additional supporting information may be found online in
the Supporting Information section at the end of the article.

**Figure S1.** *De novo* molecular high grade (MHG) diffuse large B-cell cell lymphoma NOS and Burkitt lymphoma overall survival curves (median age at diagnosis); patients treated with curative intent, Haematological Malignancy Research Network (HMRN) diagnoses 2004–2015.

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**Dose-limiting stomatitis associated with ibrutinib therapy: a case series**

Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor approved by the European Medicines Agency and US Food and Drug Administration, is effective for patients with chronic lymphocytic leukaemia (CLL), relapsed mantle cell lymphoma and Waldenström macroglobulinemia (Byrd et al, 2013, 2014; Burger et al, 2015; Puła et al, 2017; Ransohoff & Kwong, 2017). Commonly reported adverse events include diarrhoea,

infection, fatigue, arthralgias, pyrexia, hypertension and neutropenia (Byrd et al, 2013, 2014; Burger et al, 2015; Puła et al, 2017; Tran & O'Brien, 2017). However, the rate of grade ≥3 adverse events remains low and treatment discontinuation due to toxicity (Byrd et al, 2013, 2014) is uncommon and mostly related to infections (Byrd et al, 2013, 2014; Burger et al, 2015; Puła et al, 2017; Tran & O'Brien, 2017).
Dermatological toxicities have also been reported in 2–27% of treated patients (Ransohoff & Kwong, 2017; Iberri *et al*, 2018), mainly mild-to-moderate rash, neutrophilic panniculitis, progressive hair and nail changes, skin infections, bruising, petechiae and purpuric eruption (Fabbro *et al*, 2015; Bitar *et al*, 2016; Ransohoff & Kwong, 2017; Iberri *et al*, 2018). In contrast, oral toxicity with ibrutinib has rarely been described. A prospective dermatological survey did not observe any mucosal involvement in a cohort of 66 consecutive patients (Bitar *et al*, 2016). However, a recent pivotal study reported all-grade and high-grade stomatitis in 11% and 1% of treated patients, respectively, but the clinical aspects were not documented (Byrd *et al*, 2014).

We report three patients (Table I) who progressively developed a grade ≥3 oral toxicity with ibrutinib monotherapy. Lesions were reminiscent of painful oral necrotic ulcers mimicking aphthous stomatitis and required treatment interruption in all cases. This case series is the first to report the clinical manifestations of grade ≥3 stomatitis induced by ibrutinib therapy.

The three patients, aged 66–78 years, were treated with oral ibrutinib (420 mg/day) as a monotherapy for the management of CLL. The time to onset of oral lesions ranged from 4 weeks to 16 months after ibrutinib initiation. Physical oral examination revealed necrotic progressive well-circumscribed mucosal ulcers of about 1 cm in diameter. They were surrounded by a brightly erythematous halo mimicking the appearance of major aphthous stomatitis. Lesions exclusively involved the nonkeratinized mucosae [tonsil, labial mucosae (Fig 1A)], ventral aspect of tongue (Fig 1B), and buccal mucosae in Patients 1 and 2 (Table I). Patient 3 (Table I) developed lesions on both nonkeratinized and keratinized mucosae, including multiple deep round ulcers on the tip and dorsal aspect of the tongue covered by a yellowish-grey pseudomembrane (Fig. 1C). All patients reported intense pain and dysphagia associated with recent weight loss. According to the National Cancer Institute Common Toxicity Criteria for Adverse Events v5.0 (https://ctep.cance.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf), this oral toxicity was grade ≥3 and required interruption of ibrutinib.

Bacterial/fungal swab cultures and *in situ* polymerase chain reaction (PCR) screening for herpes simplex virus 1 and 2, varicella zoster virus and cytomegalovirus were negative in all cases. In addition, quantitative PCR in blood samples for Epstein-Barr Virus, parvovirus and human herpesvirus 6 were negative. Finally, no grade ≥2 neutropenia was noted.

The mucosal lesions rapidly resolved within a week in all patients after treatment discontinuation and supportive care including basic oral care, corticosteroids (prednisone mouthwash, topical application of clobetasol cream and/or systemic corticosteroids with prednisolone 1 mg/kg/day) (Fig 1D) and photobiomodulation (low-level laser therapy, power 150 mW; wavelength 660 nm, 4 J/cm²).

In one patient, a rechallenge with ibrutinib at the same dose (420 mg/day) resulted in the development of similar oral lesions within 5 days. Ibrutinib was therefore reinitiated at a lower dose (280 mg/day), without any recurrence. Similarly, ibrutinib was reinitiated at a lower dose (280 mg/day) in the other two patients without any recurrence of oral toxicity.

The clinical presentation of ibrutinib-associated stomatitis clearly differs from mucositis induced by chemotherapeutic agents, usually starting with distinct ulcerations that ultimately become diffuse, poorly circumscribed and confluent. Moreover, chemo-induced mucositis appears 4–7 days after the first cycle (Vigarios *et al*, 2017) and solely involves nonkeratinized mucosae. Aphthous-like lesions on nonkeratinized mucosa have been previously reported with other therapies targeting different kinase pathways, especially mammalian target of rapamycin (mTOR) inhibitors. We also recently characterized similar mucosal involvement with several other tyrosine kinase inhibitors (TKIs) targeting human epidermal growth factor receptor (HER) (HER1-erlotinib, gefitinib, pan HER-afatinib, dacomitinib) or with multikinase angiogenesis inhibitors (*sorafenib, sunitinib, pazopanib*) (Vigarios *et al*, 2017).

The pathogenesis of ibrutinib-associated dermatological toxicities remains to be elucidated (Fabbro *et al*, 2015). It would be reminiscent of a localized adaptive cellular immune response where ibrutinib-conjugated peptides would be presented to host immune cells via a major histocompatibility complex, leading to a T-cell-driven immune response and bystander tissue destruction (Fabbro *et al*, 2015). Moreover, although ibrutinib demonstrates high selectivity for BTK, it also exerts off-target effects on other kinases, including irreversible binding to epidermal growth factor receptor (EGFR) or HER2 (Bitar *et al*, 2016). This mechanism could partly explain the pathogenesis of ibrutinib-associated oral ulcers, even though anti-EGFR-related mucositis mostly occurs in the first weeks of treatment, solely involves nonkeratinized mucosae (similar to other kinase inhibitors, including mTOR inhibitors) and remains of low grade (Vigarios *et al*, 2017).

Oral aphthous-like ulcers have also been reported in haematological patients with concomitant neutropenia. However, no correlation with neutropenia could be established in our patients who presented a normal range of neutrophils (Table I). In addition, an infectious origin remains very unlikely, because the lesions clearly improved with corticosteroids and bacterial or viral swabs were negative in all cases.

In conclusion, ibrutinib can trigger severe impairing stomatitis that may require temporary discontinuation of the drug. Lesions can develop only after several months of treatment and can involve keratinized mucosa, which is unusual in comparison with the aphthous-like ulcers observed with other TKIs. In our experience, topical or short courses of systemic corticosteroids should be recommended for managing oral ulcers and relieving pain, once an active infection has been ruled out. The clinical
<table><caption>Table I. Clinical features of chronic lymphocytic leukaemia patients developing severe stomatitis with ibrutinib monotherapy.</caption><thead><tr><th>Patient/sex/age (years)</th><th>Time to onset after ibrutinib introduction</th><th>Location of aphthous-like lesions</th><th>Stomatitis grade*</th><th>Other dermatological adverse events</th><th>ANC (×10<sup>9</sup>/l)†</th><th>Treatment</th><th>Clinical outcome</th></tr></thead><tbody><tr><td>1/male/66</td><td>16 months</td><td>Mainly located on the lip mucosae, tonsil and ventral aspect of the tongue (nonkeratinized mucosae)</td><td>4</td><td>-</td><td>1.6</td><td><strong>Interruption of ibrutinib</strong><br><em>Symptomatic management:</em><br><ul><li>predisolone mouthwash, three times a day</li></ul></td><td>Healing of oral mucosal lesions<br>3 days after ibrutinib interruption<br>2 weeks later, rechallenge at the same dose was followed by development of new similar mucosal lesions in 5 days</td></tr><tr><td>2/female/66</td><td>4 weeks</td><td>Mainly located on the ventral aspect of the tongue and the buccal mucosae (nonkeratinized mucosae)</td><td>3</td><td>Grade 1-2 cutaneous ecchymotic lesions and follicular pustulosis on the limbs, with staphylococcus aureus superinfection</td><td>1.45</td><td><strong>Interruption of ibrutinib</strong><br><em>Symptomatic management:</em><br><ul><li>basic oral care,</li><li>topical corticosteroids (clobetasol cream), twice a day</li><li>photobiomodulation</li></ul></td><td>Reintroduction at lower dose (280 mg/day) a few days later, without recurrence of oral lesions<br>1 week<br>Ibrutinib was reinitiated at lower dose (280 mg/day) without recurrence</td></tr><tr><td>3/female/78</td><td>7 months</td><td>Lesions developed on both keratinized mucosae (the dorsum and tip of the tongue) and nonkeratinized mucosa (ventral aspect of the tongue and the lip mucosa)</td><td>3/4</td><td>Grade 2 cutaneous ecchymotic lesions located on the limbs</td><td>3.3</td><td><strong>Interruption of ibrutinib</strong><br><em>Symptomatic management:</em><br><ul><li>basic oral care,</li><li>short course of systemic corticosteroids (prednisolone 1 mg/kg/day, 5 days)</li></ul></td><td>Healing of mucosal lesions within 1 week<br>Ibrutinib was reinitiated at lower dose (280 mg/day) without recurrence</td></tr></tbody></table>

<footnote>* According to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0; https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick Reference_8.5x11.pdf.</footnote>

<footnote>† Absolute neutrophil count when stomatitis occurred.</footnote>
Fig 1. (A) Circumscribed major necrotic ulcer with erythematous halo located on lip mucosa (Patient 1). (B) Mucosal lesions located on ventral aspect of tongue, mimicking major aphthous stomatitis and surrounded by erythematous halo with visible yellow fibrinous coating base (Patient 2). (C) Multiple painful aphthous-like lesions with circumscribed margins, erythematous halo, on dorsum and tip of tongue (keratinized mucosae) (Patient 3). (D) Significant improvement in Patient 3 5 days after ibrutinib discontinuation and a short course of systemic prednisolone. [Colour figure can be viewed at wileyonlinelibrary.com]

<figure><img src="image_1.png" /></figure>

outcomes observed in our patients suggest that ibrutinib may be resumed at a lower dose, without any recurrence.

## Declarations

The contents of this manuscript are our original work and have not been published, in whole or in part, prior or simultaneous with this current submission. The manuscript has been read and approved for submission by all authors and all persons listed as authors have contributed to preparing the manuscript. The authors do not declare major conflict of interest related to the submitted work.

## Funding

None.

Emmanuelle Vigarios¹

<figure><img src="image_2.png" /></figure>

Marie Beylot-Barry²

Marie-Hélène Jegou³

Luice Oberic⁴

Loïc Ysebaert⁴

Vincent Sibaud¹,⁵

¹Oral Medicine Department, Institut Claudius Regaud, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, ²Onco-Dermatology Department, Hôpital Saint-André, INSERM U1053, Oncogenesis of Cutaneous Lymphoma, Bordeaux, ³Dermatology, Blanquefort,

⁴Haematology Department, Institut Universitaire du cancer Toulouse-Oncopole, and ⁵Onco-Dermatology and Clinical research Department, Institut Claudius Regaud, Institut Universitaire du cancer Toulouse-Oncopole, Toulouse, France.

E-mail: vigarios.emmanuelle@iuct-oncopole.fr

**Keywords:** ibrutinib, stomatitis, oral ulcer, mucositis, chronic lymphocytic leukaemia

First published online 8 November 2018

doi: 10.1111/bjh.15620

## References

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Burger, J.A., Tedeschi, A., Barr, P.M., Robak, T., Owen, C., Ghia, P., Bairey, O., Hillmen, P., Bartlett, N.L., Li, J., Simpson, D., Grosicki, S., Devereux, S., McCarthy, H., Coutre, S., Quach, H.,

Gaidano, G., Maslyak, Z., Stevens, D.A., Janssens, A., Offner, F., Mayer, J., O'Dwyer, M., Hellmann, A., Schuh, A., Siddiqi, T., Polliack, A., Tam, C.S., Suri, D., Cheng, M., Clow, F., Styles, L., James, D.F., Kipps, T.J. & RESONATE-2 Investigators. (2015) Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. *New England Journal of Medicine*, **373**, 2425–2437.

Byrd, J.C., Furman, R.R., Coutre, S.E., Flinn, I.W., Burger, J.A., Blum, K.A., Grant, B., Sharman, J.P., Coleman, M., Wierda, W.G., Jones, J.A.,

Zhao, W., Heerema, N.A., Johnson, A.J., Sukbuntherng, J., Chang, B.Y., Clow, F., Hedrick, E., Buggy, J.J., James, D.F. & O'Brien, S. (2013) Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. *New England Journal of Medicine*, **369**, 32–42.

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# Low risk of *Pneumocystis jirovecii* pneumonia and invasive aspergillosis in patients with Waldenström macroglobulinaemia on ibrutinib

Waldenström macroglobulinaemia (WM) is a B cell lymphoma that is commonly associated with the activation of nuclear factor-κB via Bruton tyrosine kinase (BTK) (Yang *et al*, 2013). Ibrutinib, a BTK inhibitor, is US Food and Drug Administration-approved for the treatment of chronic lymphocytic leukaemia (CLL), mantle cell lymphoma, marginal zone lymphoma and WM (https://www.imbruvica.com/docs/librariesprovider7/default-document-library/prescribing-infoproduction.pdf).

Patients with CLL and other lymphoid malignancies receiving ibrutinib therapy are at risk for developing invasive fungal disease (IFD), including *Pneumocystis jirovecii* pneumonia (PCP) and invasive aspergillosis (IA) (Arbona-Haddad *et al*, 2018; Varughese *et al*, 2018). Most patients who develop these infections while on ibrutinib do not exhibit classical risk factors for IFD, such as neutropenia, lymphopenia or corticosteroid treatment (Varughese *et al*, 2018).

Fungal infections in patients with CLL and other lymphoid malignancies receiving ibrutinib may be due to the off-target effect of the drug on the adaptive immune system (Lionakis *et al*, 2017). Whether this increased risk of infection is caused by ibrutinib alone or in combination with immune dysregulation from the underlying malignancy is unknown. The objective of this study was to assess the risk of PCP and IA in WM patients receiving ibrutinib, in order to guide decisions regarding antimicrobial prophylaxis.

A retrospective study was performed of all adult patients with WM who initiated ibrutinib at Dana-Farber Cancer Institute (DFCI) between 28 May 2012 and 30 January 2018. Patients were followed until 1 April 2018 for the development of PCP and IA. The study was approved by the Dana-

Farber/Harvard Cancer Center Office for Human Research Studies.

Covariates of interest included patient age, sex, previous treatment regimens, antimicrobial medications, and length of exposure to ibrutinib. In- and out-patient medical records were reviewed for cases of PCP and IA. These records were reviewed for exposure to prophylactic or treatment agents to these pathogens, including atovaquone, trimethoprim-sulfamethazole, voriconazole, posaconazole, and isavuconazole.

Invasive fungal disease was assessed by two infectious diseases specialists and was classified per the European Organization for Research and Treatment of Cancer (EORTC)/Invasive Fungal Infections and Mycoses Study Group (IFI and MSG) (De Pauw *et al*, 2008). Patients who participated in clinical trials at DFCI had adverse events-reporting logs verified to ensure completeness of data collection. We calculated exact 95% confidence limits for the binomial proportion (Clopper & Pearson, 1934) using SAS® 9.4 (SAS Institute, Cary, NC, USA).

In total, 217 WM patients were treated with ibrutinib during the study period. Their baseline and clinical characteristics are presented in Table I. One hundred and forty (65%) were male, and the median age at initiation of ibrutinib was 67 years (range, 43–93). Ibrutinib was initially prescribed at a dose of 420 mg/day in all patients and was administered in a continuous fashion. Fifty-eight patients (27%) had a dose reduction due to adverse events or interactions with concomitant medications; 46 (21%) to 280 mg/day and 12 (6%) to 140 mg/day. No patient received concomitant immunosuppressive therapy; 153 patients (71%) had been treated with different chemotherapeutic regimens prior to starting ibrutinib, with a median of two (range, one to eight) previous treatment regimens (Table I).