Avoidance of surgery for head and neck infantile myofibromatosis using imatinib monotherapy

Abstract Describe a novel use for a kinase inhibitor, imatinib, in young children with a known activated somatic mutation in PDGFR‐beta. Two patients with infantile myofibromatosis treated with imatinib. Case description of evaluation, diagnosis and treatment decisions for infantile myfibromatosis of the head and neck. Description of medical therapy for infantile myofibromatosis in these patients. For function threatening myofibromas of a known genotype, in infants, targeted medical therapy is a treatment option.


| INTRODUCTION
Infantile myofibromatosis (IM) is a rare proliferative disorder characterized by the growth of soft tissue neoplasms or myofibromas. As the most common soft tissue tumor in children, myofibromas occur in 1/400,000 births. 1 The associated lesions appear at birth in 60% of cases, with 88% appearing by two years of age. One-third of cases occur in the head and neck region. 2 Gain-of-function pathogenic variants of the PDGFRB gene, coding for the plateletderived growth factor receptor β (PDGFR-β) tyrosine kinase, have been implicated in IM, distinguishing them from other types of fibromatosis. Recently, tyrosine kinase inhibitors such as sorafenib and imatinib have been used in conjunction with traditional chemotherapy and surgery to control an aggressive case of IM. 3 In this report, we present two cases of IM with head and neck manifestations in which surgery was avoided through treatment with imatinib monotherapy. These patients were recently described as part of a larger series on PDGFRB activating variant spectrum disorder (PAVS). PAVS1 encompasses IM and aneurysms, while PAVS2 includes Penttinen syndrome and Kosaki overgrowth syndrome. 4 2 | CASE REPORTS 2.1 | Patient 1 Patient 1 was born at 38 6/7 weeks gestation to a family with a history of myofibromatosis. He was born with extensive cutaneous nodules that on biopsy were consistent with myofibroma ( Figure 1A). Genetic testing of tissue and peripheral blood (UW-OncoPlex Cancer Gene Panel 5 ) revealed activating pathogenic PDGFRB variants. Peripheral blood demonstrated p.R561C variant, while tumor tissue demonstrated both p.R561C and p.N666K variants. Magnetic resonance imaging (MRI) at two weeks of age confirmed myofibromas in the facial, neck, chest wall, paraspinous, and extremity soft tissues.
A large tongue myofibroma measuring 1.9 cm was demonstrated on the MRI (Figure 2A, B). As the lesion grew, his symptoms escalated from feeding difficulties to airway obstruction, necessitating continuous positive airway pressure (CPAP) ventilation. Direct laryngoscopy and bronchoscopy revealed airway compromise due to the myofibroma located at the base of tongue (Cormack-Lehane Grade IV laryngeal view), without other airway masses or causes for airway obstruction.
Due to progressive aerodigestive tract compromise at 4 weeks old, imatinib was started (6 mg/kg/day). Subcutaneous and tongue lesions decreased in size, and airway compromise improved. After three weeks of imatinib treatment, all respiratory and oxygen support were weaned off. After a month, he was discharged from the hospital, with the tongue lesion barely palpable. He underwent monthly dose adjustments for weight as an outpatient. Imatinib was discontinued after fourteen weeks, with MRI at that time demonstrating near-complete resolution of all cutaneous lesions and resolution of the tongue lesion. Over the next nine months of follow-up of imatinib, there was interval regrowth of the cutaneous and muscular nodules clinically and on MRI, but not of the tongue lesion ( Figure 1C). The family elected to observe the other lesions.

| Patient 2
Patient 2 was born at 35 4/7 weeks via Caesarian section because of a prenatally diagnosed, large solid, partially necrotic right facial mass ( Figure 3A, B). Imaging also demonstrated focal skeletal lucencies. Incisional biopsy and debridement of the facial mass were performed on Day six of life. The mass developed a non-healing ulcerative, necrotic wound requiring wound care and admission for secondary infection ( Figure 3C, D). Histologically, the biopsy confirmed myofibroma ( Figure 1B). Genetic testing (UW OncoPlex 5 ) of peripheral blood was negative for germline changes in PDGFRB, but two somatic variants were noted in the tissue sample (p.I564_V572del and p.N666T).
At 35 days old, imatinib was started (6 mg/kg/day). Response was brisk, with flattening and healing of the ulcerated mass over the next 2 months (Figure 3E, F). During that same time, MRI and skeletal survey demonstrated resolution or improvement of soft tissue and bony lesions. The patient remained on therapy for 5 months. During the last two months of treatment, she required fortified formula supplementation due to slowed weight gain.

| DISCUSSION
IM (or PAVS1) can be a devastating disease affecting children less than two years old. Approximately one-third of cases involve the head and neck and can occur in any subsite, making the disease of considerable importance to otolaryngologists. 2 Given that many such lesions will regress over time, traditional management includes observation for quiescent lesions, while surgery or chemotherapy has been used for growing myofibromas. 6,7 In neonates and infants, either surgical excision of large infiltrative head and neck masses or chemotherapy is highly morbid. 8 In our two patients, the myofibromas were not quiescent and surgical resection would have been extensive and would have probably required repeated procedures, with significant functional consequences. In these patients, it was thought that targeted medical therapy directed at the causal activated gene variant would have less risk and be more effective than traditional therapies. The treatment plan was supported by in vitro evidence, 9,10 a prior case of imatinib and sorafenib in combination with traditional chemotherapy, 3 and experience with other PDGFRB-mediated conditions. 4 Major surgeries were avoided in both instances. In Patient 1, worsening airway obstruction requiring positive-pressure ventilation would have ultimately required tracheostomy. In patient 2, the non-healing ulcerated myofibroma healed and regressed, so that extensive surgery and reconstruction were unnecessary. We have demonstrated that imatinib offers a new and effective therapy for selected IM patients by targeting their known activating PDGFRB variants.
Further research is needed to understand optimal treatment duration and risks in this population. It is noteworthy that for Patient 1, improvements in the tongue myofibroma were clinically durable after imatinib cessation, while cutaneous and other soft tissue lesions were not. For Patient 2, long-term assessment was not possible. Given the dramatic results seen in our patients, imatinib monotherapy should be considered prior to surgery or chemotherapy for patients with activating variants in PDGFRB. It is possible that adjunctive use of tyrosine kinase inhibitors will allow for more targeted surgical approach to myofibromas. Adverse events, such as decreased growth velocity or dermatitis, cannot be fully ascertained in this limited study. 4 These risks warrant further study.

| CONCLUSION
Frequently causing myofibromas in the head and neck, IM can be devastating, but the recognition that it is caused by gain-of-function variants in the PDGFR-β tyrosine kinase receptor has led to a unique opportunity for precision medicine. Recent literature supports the use of imatinib and other tyrosine kinase inhibitors in the treatment of IM. Our experience treating two infants with myofibromas using imatinib monotherapy suggests that targeted treatment of PAVS1 may be a safe and effective to manage these patients, avoiding surgery or chemotherapy. Further research is required to determine optimal treatment duration and potential adverse events for patients on this targeted therapy.