Ocular Findings in Neurofibromatosis

**73**

**Chapter 5**

**Abstract**

**1. Introduction**

may be seen in some.

**2. Types of neurofibromatosis**

Ocular Findings in

Neurofibromatosis

*Hind M. Alkatan, Sawsan S. Bakry* 

*and Mohammad A. Alabduljabbar*

Neurofibromatosis (NF) is an inherited disease affecting multiple systems in the body. The eye is frequently affected in neurofibromatosis, and therefore ocular manifestations play a major role in the diagnosis of NF. This chapter aims to explore the spectrum of ocular manifestations found in neurofibromatosis highlighting the importance of ophthalmic exam in these patients. It will describe various intraocular manifestations involving the iris, lens, and retina. It will be focusing on glaucoma and the pathogenesis behind it in this group of patients. Moreover, periorbital and orbital involvement such as skin neurofibromas and optic nerve gliomas will be

**Keywords:** neurofibromatosis, glaucoma, cataract, retinal hamartoma, Lisch nodules,

Neurofibromatosis (NF) is an inherited disease affecting multiple systems in the body. It is caused by a genetic mutation affecting cellular growth regulation, therefore resulting in disrupted pathways and formation of multiple tumors in the body. Ocular involvement is an important part of the disease as it may be required for the diagnosis. Although some manifestations are only of diagnostic value such as Lisch nodules, other ocular involvement can be vision threatening like glaucoma and optic nerve gliomas. Therefore, this chapter aims to explore how this disease can affect various structures of the eye and some histopathological changes that

Neurofibromatosis is caused by a gene mutation affecting a tumor suppressor protein resulting in uncontrolled proliferation of neural cells that can involve various parts of the body such as nerves, skin, and eyes. It is classified into two types based on the location of the mutated gene. Neurofibromatosis type 1 (NF-1), also known as von Recklinghausen disease, is caused by a mutation in the gene NF-1 located on chromosome 17. This leads to a dysfunctional tumor suppressor protein known as neurofibromin. As a result, NF-1 manifests as multiple benign tumors in the body such as plexiform neurofibromas, Lisch nodules, and optic nerve gliomas.

choroid, optic nerve, glioma, plexiform neurofibroma, diffuse neurofibroma

discussed along with some of their histopathological findings.

#### **Chapter 5**

## Ocular Findings in Neurofibromatosis

*Hind M. Alkatan, Sawsan S. Bakry and Mohammad A. Alabduljabbar*

#### **Abstract**

Neurofibromatosis (NF) is an inherited disease affecting multiple systems in the body. The eye is frequently affected in neurofibromatosis, and therefore ocular manifestations play a major role in the diagnosis of NF. This chapter aims to explore the spectrum of ocular manifestations found in neurofibromatosis highlighting the importance of ophthalmic exam in these patients. It will describe various intraocular manifestations involving the iris, lens, and retina. It will be focusing on glaucoma and the pathogenesis behind it in this group of patients. Moreover, periorbital and orbital involvement such as skin neurofibromas and optic nerve gliomas will be discussed along with some of their histopathological findings.

**Keywords:** neurofibromatosis, glaucoma, cataract, retinal hamartoma, Lisch nodules, choroid, optic nerve, glioma, plexiform neurofibroma, diffuse neurofibroma

#### **1. Introduction**

Neurofibromatosis (NF) is an inherited disease affecting multiple systems in the body. It is caused by a genetic mutation affecting cellular growth regulation, therefore resulting in disrupted pathways and formation of multiple tumors in the body. Ocular involvement is an important part of the disease as it may be required for the diagnosis. Although some manifestations are only of diagnostic value such as Lisch nodules, other ocular involvement can be vision threatening like glaucoma and optic nerve gliomas. Therefore, this chapter aims to explore how this disease can affect various structures of the eye and some histopathological changes that may be seen in some.

#### **2. Types of neurofibromatosis**

Neurofibromatosis is caused by a gene mutation affecting a tumor suppressor protein resulting in uncontrolled proliferation of neural cells that can involve various parts of the body such as nerves, skin, and eyes. It is classified into two types based on the location of the mutated gene. Neurofibromatosis type 1 (NF-1), also known as von Recklinghausen disease, is caused by a mutation in the gene NF-1 located on chromosome 17. This leads to a dysfunctional tumor suppressor protein known as neurofibromin. As a result, NF-1 manifests as multiple benign tumors in the body such as plexiform neurofibromas, Lisch nodules, and optic nerve gliomas.


**Table 1.**


NF-1 is inherited as autosomal dominant trait but may be sporadic in about 50% of the cases [1]. Ophthalmic manifestations are of diagnostic value in NF. **Table 1** shows the criteria that are used for the diagnosis of NF-1 [2]. Three out of the total seven may involve ocular structures. Therefore, an individual may be diagnosed with NF-1 solely on his ophthalmic exam.

Neurofibromatosis type 2 (NF-2) is caused by a chromosome 22 mutation in the gene encoding for the protein merlin or schwannomin, which is also a tumor suppressor protein. Dysregulation of this gene results in overproduction of Schwann cells. Therefore, the most prominent feature of this disease is bilateral vestibular schwannomas occurring in almost 90% of the patients. It may also affect different structures in the body causing tumors such as optic meningiomas and gliomas. Similar to NF-1, it is inherited in autosomal dominant fashion but may be sporadic [2].

Clinical presentation of both diseases may overlap as they both affect cellular growth of neural tissue. This chapter will be discussing ocular manifestations that are seen in NF highlighting the importance of ophthalmic examination in these patients.

#### **3. Intraocular manifestations**

#### **3.1 Iris**

Various intraocular conditions have been described in NF, most commonly, iris hamartomas. Iris hamartomas is a hallmark feature in NF-1 and is therefore considered one of the diagnostic criteria. Histologically, Lisch nodules have been described to be a collection of spindle cells that are melanocytic in origin [3]. They usually occur during childhood and increase in size and number with aging. They are typically seen under slit-lamp examination; are described as round elevated nodules within the iris, measuring around 2–3 mm in size; and are brown to yellow in color (**Figure 1**). Lisch nodules are typically bilateral; however, unilateral nodules have been reported previously in some types of NF [4].

#### **3.2 Glaucoma**

Glaucoma has been found to occur in about 1 in 300 NF-1 patients [5]. Patients with orbito-facial involvement have been linked to higher rates of glaucoma at 23–50% [6–8]. It was also found that patients with eyelid plexiform neurofibromas have ipsilateral globe enlargement up to 36 mm axial length [6]. Although glaucoma

**75**

*Ocular Findings in Neurofibromatosis*

in the angle [7].

**Figure 1.**

above.

**3.3 Lens**

**3.4 Retina and choroid**

*DOI: http://dx.doi.org/10.5772/intechopen.90021*

in NF is not common, it has been studied due to the visual burden it may cause. Various mechanisms have been described in the pathogenesis of glaucoma in these patients. The most commonly described mechanism is the presence of neurofibromas in the angle causing aqueous outflow obstruction [6]. Other suggested processes include secondary angle closure due to the anterior displacement of the peripheral iris by an abnormally thickened ciliary body or developmental anomalies

*Slit-lamp photo of an iris showing Lisch nodules in a patient diagnosed with neurofibromatosis.*

Moreover, congenital ectropion uvea has been linked to refractory glaucoma in patients with NF. Histologically, endothelialization of the anterior chamber angle has been observed in these eyes. It has been hypothesized that loss of the NF gene and therefore RAS–RAF–ERK–MAPK pathway activation may be the cause of endothelial overgrowth in these patients [9]. It is difficult to link one mechanism causing glaucoma in NF as most cases are probably multifactorial as described

Lens opacities are of importance in NF-2 as they may be the first sign to suggest the diagnosis during childhood [10]. NF-2 typically causes posterior subcapsular cataract

Retinal astrocytic hamartomas are benign tumors that usually affect the optic nerve. They clinically resemble a small white mulberry and are mostly linked to tuberous sclerosis but have been reported in NF patients as well. Rarely, those lesions may extend to the peripheral retina and cause devastating complications such as neovascular glaucoma and retinal detachment. Other retinal lesions described in NF patients include combined hamartoma of the retina and retinal pigment epithelium (CHR-RPE) and retinal capillary hemangiomatosis [12–14]. In the past, choroidal involvement was thought to be uncommon in NF patients as it was difficult to visualize subtle changes with fundus examination and conventional angiography. However, with the development of new diagnostic technologies such as optical coherence tomography (OCT), choroidal changes have been found to reach up to 100% of NF patients [15]. Uveal neurofibromatosis has been also

or cortical cataract and occurs in 60–80% of patients with the disease [10, 11].

demonstrated histopathologically within the choroid (**Figure 2**) [9].

*Neurofibromatosis - Current Trends and Future Directions*

Two or more neurofibromas of any type or one plexiform neurofibroma

A distinctive osseous lesion (sphenoid dysplasia or tibial pseudarthrosis)

postpubertal individuals)

Optic glioma

**Table 1.**

Axillary or inguinal freckling.

A first degree relative with NF1

Two or more Lisch nodules (iris hamartomas)

*Diagnostic criteria for NF1 (two or more must be present).*

with NF-1 solely on his ophthalmic exam.

may be sporadic [2].

**3. Intraocular manifestations**

have been reported previously in some types of NF [4].

patients.

**3.1 Iris**

NF-1 is inherited as autosomal dominant trait but may be sporadic in about 50% of the cases [1]. Ophthalmic manifestations are of diagnostic value in NF. **Table 1** shows the criteria that are used for the diagnosis of NF-1 [2]. Three out of the total seven may involve ocular structures. Therefore, an individual may be diagnosed

Six or more café au lait macules (greatest diameter of >5 mm in prepubertal individuals and > 15 mm in

Neurofibromatosis type 2 (NF-2) is caused by a chromosome 22 mutation in the gene encoding for the protein merlin or schwannomin, which is also a tumor suppressor protein. Dysregulation of this gene results in overproduction of Schwann cells. Therefore, the most prominent feature of this disease is bilateral vestibular schwannomas occurring in almost 90% of the patients. It may also affect different structures in the body causing tumors such as optic meningiomas and gliomas. Similar to NF-1, it is inherited in autosomal dominant fashion but

Clinical presentation of both diseases may overlap as they both affect cellular growth of neural tissue. This chapter will be discussing ocular manifestations that are seen in NF highlighting the importance of ophthalmic examination in these

Various intraocular conditions have been described in NF, most commonly, iris hamartomas. Iris hamartomas is a hallmark feature in NF-1 and is therefore considered one of the diagnostic criteria. Histologically, Lisch nodules have been described to be a collection of spindle cells that are melanocytic in origin [3]. They usually occur during childhood and increase in size and number with aging. They are typically seen under slit-lamp examination; are described as round elevated nodules within the iris, measuring around 2–3 mm in size; and are brown to yellow in color (**Figure 1**). Lisch nodules are typically bilateral; however, unilateral nodules

Glaucoma has been found to occur in about 1 in 300 NF-1 patients [5]. Patients with orbito-facial involvement have been linked to higher rates of glaucoma at 23–50% [6–8]. It was also found that patients with eyelid plexiform neurofibromas have ipsilateral globe enlargement up to 36 mm axial length [6]. Although glaucoma

**74**

**3.2 Glaucoma**

in NF is not common, it has been studied due to the visual burden it may cause. Various mechanisms have been described in the pathogenesis of glaucoma in these patients. The most commonly described mechanism is the presence of neurofibromas in the angle causing aqueous outflow obstruction [6]. Other suggested processes include secondary angle closure due to the anterior displacement of the peripheral iris by an abnormally thickened ciliary body or developmental anomalies in the angle [7].

Moreover, congenital ectropion uvea has been linked to refractory glaucoma in patients with NF. Histologically, endothelialization of the anterior chamber angle has been observed in these eyes. It has been hypothesized that loss of the NF gene and therefore RAS–RAF–ERK–MAPK pathway activation may be the cause of endothelial overgrowth in these patients [9]. It is difficult to link one mechanism causing glaucoma in NF as most cases are probably multifactorial as described above.

#### **3.3 Lens**

Lens opacities are of importance in NF-2 as they may be the first sign to suggest the diagnosis during childhood [10]. NF-2 typically causes posterior subcapsular cataract or cortical cataract and occurs in 60–80% of patients with the disease [10, 11].

#### **3.4 Retina and choroid**

Retinal astrocytic hamartomas are benign tumors that usually affect the optic nerve. They clinically resemble a small white mulberry and are mostly linked to tuberous sclerosis but have been reported in NF patients as well. Rarely, those lesions may extend to the peripheral retina and cause devastating complications such as neovascular glaucoma and retinal detachment. Other retinal lesions described in NF patients include combined hamartoma of the retina and retinal pigment epithelium (CHR-RPE) and retinal capillary hemangiomatosis [12–14].

In the past, choroidal involvement was thought to be uncommon in NF patients as it was difficult to visualize subtle changes with fundus examination and conventional angiography. However, with the development of new diagnostic technologies such as optical coherence tomography (OCT), choroidal changes have been found to reach up to 100% of NF patients [15]. Uveal neurofibromatosis has been also demonstrated histopathologically within the choroid (**Figure 2**) [9].

#### **Figure 2.**

*The choroid in a neurofibroma patient with spindle and ganglion cells (original magnification X400 hematoxylin and eosin).*

### **4. Periocular and orbital manifestations**

#### **4.1 Optic pathway glioma**

Optic pathway gliomas are low-grade tumors which are classified as WHO grade I pilocytic astrocytomas. They usually occur early in childhood in around 5–25% of NF patients [15]. Although benign, these tumors can cause significant visual loss due to the direct compression of the optic nerve. They may arise anywhere along the optic pathway from the optic nerve to the chiasm and radiation. When those tumors involve the orbit, they may cause unilateral proptosis, strabismus, and decreased vision. Due to the nature of these tumors and the catastrophic consequences they may have, annual screening for all NF patients less than 10 years of age and then every 2 years until the age of 18 years is recommended [16].

#### **4.2 Orbital-periorbital plexiform neurofibroma (OPPN)**

One of the most characteristic findings in NF-1 patients and a hallmark of the disease is plexiform neurofibroma. It is a congenital tumor usually unilateral involving the eyelid, orbit, and periorbital area. It starts early in childhood with rapid growth that slows down after puberty. OPPN affects approximately 10% of patients with NF-1, and it carries a risk for malignant transformation in about 10%. It is considered a benign tumor of peripheral nerves with spindle cell proliferation and wavy filamentous pattern of growth (**Figures 3** and **4**). Histologically, they may be composed of mixed diffuse and plexiform types (**Figure 5**) with proliferation of Schwann cells, fibroblasts, and mast cells. Plexiform neurofibromas are similar but are encapsulated with the proliferations being surrounded by perineurium (**Figure 6**). Plexiform neurofibromas are of clinical significance as they are often described clinically as a "bag of worms" and can grow to form bulging masses that can be quiet disfiguring to a patient leading to social embarrassment. They usually cause mechanical ptosis when involving the upper eyelid (**Figure 7**), which may lead to amblyopia in children. Further progression to orbital and periorbital areas lead to proptosis, strabismus, and displacement of the globe. Rarely, plexiform neurofibromas may also involve the conjunctiva of the eye. Sphenoid wing dysplasia can be found in patients with OPPN affecting the same side and usually present with proptosis and pulsatile exophthalmos. Plexiform neurofibroma is a highly recurrent tumor, especially in orbito-facial area and in younger patients [17–19].

**77**

**Figure 5.**

*magnification X100 hematoxylin and eosin).*

*Ocular Findings in Neurofibromatosis*

**Figure 3.**

**Figure 4.**

*magnification X200 S-100).*

*hematoxylin and eosin).*

*DOI: http://dx.doi.org/10.5772/intechopen.90021*

*Neurofibroma of the diffuse type with spindle cell proliferation (original magnification X400* 

*The same diffuse type of neurofibroma with spindle cells expressing s-100 staining (original* 

*Mixed plexiform (black star) and diffuse (red arrowhead) neurofibromatosis (original* 

*Ocular Findings in Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.90021*

*Neurofibromatosis - Current Trends and Future Directions*

**4. Periocular and orbital manifestations**

every 2 years until the age of 18 years is recommended [16].

**4.2 Orbital-periorbital plexiform neurofibroma (OPPN)**

Optic pathway gliomas are low-grade tumors which are classified as WHO grade I pilocytic astrocytomas. They usually occur early in childhood in around 5–25% of NF patients [15]. Although benign, these tumors can cause significant visual loss due to the direct compression of the optic nerve. They may arise anywhere along the optic pathway from the optic nerve to the chiasm and radiation. When those tumors involve the orbit, they may cause unilateral proptosis, strabismus, and decreased vision. Due to the nature of these tumors and the catastrophic consequences they may have, annual screening for all NF patients less than 10 years of age and then

*The choroid in a neurofibroma patient with spindle and ganglion cells (original magnification X400* 

One of the most characteristic findings in NF-1 patients and a hallmark of the disease is plexiform neurofibroma. It is a congenital tumor usually unilateral involving the eyelid, orbit, and periorbital area. It starts early in childhood with rapid growth that slows down after puberty. OPPN affects approximately 10% of patients with NF-1, and it carries a risk for malignant transformation in about 10%. It is considered a benign tumor of peripheral nerves with spindle cell proliferation and wavy filamentous pattern of growth (**Figures 3** and **4**). Histologically, they may be composed of mixed diffuse and plexiform types (**Figure 5**) with proliferation of Schwann cells, fibroblasts, and mast cells. Plexiform neurofibromas are similar but are encapsulated with the proliferations being surrounded by perineurium (**Figure 6**). Plexiform neurofibromas are of clinical significance as they are often described clinically as a "bag of worms" and can grow to form bulging masses that can be quiet disfiguring to a patient leading to social embarrassment. They usually cause mechanical ptosis when involving the upper eyelid (**Figure 7**), which may lead to amblyopia in children. Further progression to orbital and periorbital areas lead to proptosis, strabismus, and displacement of the globe. Rarely, plexiform neurofibromas may also involve the conjunctiva of the eye. Sphenoid wing dysplasia can be found in patients with OPPN affecting the same side and usually present with proptosis and pulsatile exophthalmos. Plexiform neurofibroma is a highly recurrent tumor, especially in orbito-facial area and in younger patients [17–19].

**4.1 Optic pathway glioma**

**Figure 2.**

*hematoxylin and eosin).*

**76**

*Neurofibroma of the diffuse type with spindle cell proliferation (original magnification X400 hematoxylin and eosin).*

#### **Figure 4.**

*The same diffuse type of neurofibroma with spindle cells expressing s-100 staining (original magnification X200 S-100).*

#### **Figure 5.**

*Mixed plexiform (black star) and diffuse (red arrowhead) neurofibromatosis (original magnification X100 hematoxylin and eosin).*

#### **Figure 6.**

*An area of typical plexiform neurofibroma (original magnification X100 hematoxylin and eosin).*

#### **Figure 7.**

*A child with a plexiform neurofibroma of the right upper eyelid causing significant ptosis that affects the visual axis.*

#### **5. Imaging**

A high-resolution magnetic resonance imaging (MRI) with and without contrast of the brain and orbits should be performed in all NF-suspected patients to confirm the diagnosis and to monitor for the progression. CT scan should be avoided if possible, because of its radiation and the risk of malignant transformation of neurofibroma [19].

#### **6. Management**

Patients with NF need a multidisciplinary team of pediatric ophthalmology, neuro-ophthalmology, oculoplastic surgeon, neuro-oncology, and genetics. All children diagnosed with NF should have regular ophthalmological examinations every 6 months until the age of visual maturation (7 years) to detect and treat amblyopia, glaucoma, or strabismus. Also, serial MRI might be needed. The frequency of examination and imaging should be tailored according to the patient needs and disease progression. Early diagnosis and management of ophthalmic related issues are important and usually treated by supportive methods.

In children, surgical interventions for neurofibroma and its related strabismus should be reserved for severe cosmesis and visually threatening conditions because of its highly recurrent nature. Adults with neurofibroma usually need an aggressive and definitive surgical approach to prevent recurrence with the possibility of

**79**

*Ocular Findings in Neurofibromatosis*

**7. Conclusion**

**Conflict of interest**

**Author details**

Hind M. Alkatan1

Saudi Arabia

University, Riyadh, Saudi Arabia

*DOI: http://dx.doi.org/10.5772/intechopen.90021*

The authors declare no conflict of interest.

\*, Sawsan S. Bakry2

3 King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia

\*Address all correspondence to: hindkatan@yahoo.com

provided the original work is properly cited.

several surgeries. The most common indications for surgical debulking are cosmetic, decreased vision, progressive involvement of a vital structure, and functional deficits. Any significant increase in the growth rate of neurofibroma that is unusual for the patient age should be worrisome for malignant transformation [19].

In conclusion, neurofibromatosis can affect the eye and ocular adnexa in various ways. It is of importance to recognize ocular involvement in such patients in order to help earlier diagnosis of treatable conditions that can be vision-threatening.

and Mohammad A. Alabduljabbar3

1 Departments of Ophthalmology and Pathology, College of Medicine, King Saud

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Neurology Department, College of Medicine, King Saud University, Riyadh,

*Ocular Findings in Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.90021*

several surgeries. The most common indications for surgical debulking are cosmetic, decreased vision, progressive involvement of a vital structure, and functional deficits. Any significant increase in the growth rate of neurofibroma that is unusual for the patient age should be worrisome for malignant transformation [19].

#### **7. Conclusion**

*Neurofibromatosis - Current Trends and Future Directions*

**78**

**5. Imaging**

*affects the visual axis.*

**Figure 7.**

**Figure 6.**

neurofibroma [19].

**6. Management**

A high-resolution magnetic resonance imaging (MRI) with and without contrast

of the brain and orbits should be performed in all NF-suspected patients to confirm the diagnosis and to monitor for the progression. CT scan should be avoided if possible, because of its radiation and the risk of malignant transformation of

*A child with a plexiform neurofibroma of the right upper eyelid causing significant ptosis that* 

*An area of typical plexiform neurofibroma (original magnification X100 hematoxylin and eosin).*

Patients with NF need a multidisciplinary team of pediatric ophthalmology, neuro-ophthalmology, oculoplastic surgeon, neuro-oncology, and genetics. All children diagnosed with NF should have regular ophthalmological examinations every 6 months until the age of visual maturation (7 years) to detect and treat amblyopia, glaucoma, or strabismus. Also, serial MRI might be needed. The frequency of examination and imaging should be tailored according to the patient needs and disease progression. Early diagnosis and management of ophthalmic related issues

In children, surgical interventions for neurofibroma and its related strabismus should be reserved for severe cosmesis and visually threatening conditions because of its highly recurrent nature. Adults with neurofibroma usually need an aggressive and definitive surgical approach to prevent recurrence with the possibility of

are important and usually treated by supportive methods.

In conclusion, neurofibromatosis can affect the eye and ocular adnexa in various ways. It is of importance to recognize ocular involvement in such patients in order to help earlier diagnosis of treatable conditions that can be vision-threatening.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Hind M. Alkatan1 \*, Sawsan S. Bakry2 and Mohammad A. Alabduljabbar3

1 Departments of Ophthalmology and Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia

2 Neurology Department, College of Medicine, King Saud University, Riyadh, Saudi Arabia

3 King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia

\*Address all correspondence to: hindkatan@yahoo.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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*Ocular Findings in Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.90021*

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*Neurofibromatosis - Current Trends and Future Directions*

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[14] Destro M. Retinal manifestations of neurofibromatosis. Archives of Ophthalmology. 1991;**109**(5):662

Zeid J. Ophthalmic manifestations in neurofibromatosis type 1. Survey of Ophthalmology. 2017;**63**(4):518-533

[16] Listernick R, Ferner R, Liu G, Gutmann D. Optic pathway gliomas in neurofibromatosis-1: Controversies and recommendations. Annals of Neurology.

Optometry. 2010;**81**(5):221-233

[15] Kinori M, Hodgson N,

2007;**61**(3):189-198

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[18] Arun KP, Thomas Joseph P, Jaishankar HP, Abhinethra MS. Von Recklinghausens disease: A series of four cases with variable expression. Journal of Oral and Maxillofacial

in Oto-Rhino-Laryngology.

[1] Thomann K, Marks E,

Health. 2011;**21**(10):459-465

[3] Williamson T, Garner A,

in neurofibromatosis type 1.

1991;**12**(1):11-17

type 1. Case Reports in Ophthalmological Medicine. 2011;**2011**(854784):1-2

type 1. Ophthalmology. 2009;**116**(9):1725-1730

[7] Thavikulwat A, Edward D, AlDarrab A, Vajaranant T.

Research. 2018;**97**(1):57-69

Pathophysiology and management of glaucoma associated with

phakomatoses. Journal of Neuroscience

[8] Kahook M, Schuman J, Epstein D. Chandler and Grant's Glaucoma. 5th ed. Baltimore: Williams & Wilkins; 2013

[9] Edward D, Morales J, Bouhenni R, Patil J, Edward P, Cummings T, et al. Congenital ectropion uvea and mechanisms of glaucoma in neurofibromatosis

McGraw-Hill; 2001

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[2] Evans D. Medical management of neurofibromatosis. Paediatrics & Child

Moore A. Structure of Lisch nodules

Ophthalmic Paediatrics and Genetics.

[4] Adams E, Stewart K, Borges O, Darling T. Multiple, unilateral Lisch nodules in the absence of other manifestations of neurofibromatosis

[5] Grant W, Walton D. Distinctive gonioscopic findings in glaucoma due to neurofibromatosis. Archives of Ophthalmology. 1968;**79**(2):127-134

[6] Morales J, Chaudhry I, Bosley T. Glaucoma and globe enlargement associated with Neurofibromatosis

**83**

Section 6

Therapeutic Development

in Neurofibromatosis

### Section 6

## Therapeutic Development in Neurofibromatosis

**85**

designs.

**Chapter 6**

**Abstract**

field of NF.

**1. Introduction**

Therapeutic Development in

Although neurofibromatosis (NF) was initially recognized in the nineteenth century, only in the past two decades we have witnessed a paradigm shift in therapeutics. This progress is driven by the increasing understanding of the natural history of the NF-associated tumors and understanding of the molecular landscape of these disorders. Multiple clinical trials have been launched evaluating non-surgical treatment modalities and more studies are in the pipeline. Recently, the NF community has adopted standardized endpoints recommended by the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration established in 2011. Such collaborations among academic, regulatory and supporting communities are crucial for providing the infrastructure needed for advancing the therapeutic development in the

**Keywords:** neurofibromatosis type I, neurofibromatosis type II, chemotherapy,

The neurofibromatoses are a heterogenous group of familial tumor predisposition syndromes that result from pathogenic variants in tumor suppressor genes leading to dysregulation in various cellular pathways. This dysregulation eventually leads to tumors of the central and peripheral nervous systems as well as multiorgan involvement. The incidence of Neurofibromatosis type 1 (NF1) is approximately 1 in every 2500–3500 births [1], while the incidence of neurofibromatosis type 2 (NF2) is approximately 1 in every 25,000–33,000 births [2]. Schwannomatosis (SWN) has been identified as a distinct entity with different genetic etiology and clinical phenotype from NF2, but it is difficult to assess the precise incidence of this condition. Although the tumors that develop most frequently in NF1, NF2 and SWN are histologically benign, they can cause significant neurologic disabilities and even mortality due to the involvement of the central and peripheral nervous systems. These tumors represent a unique therapeutic challenge due to the heterogeneity in severity and rate of progression among patients and hence novel therapeutic approaches are needed. In this chapter, we will review the recent studies in the field of neurofibromatosis therapeutics along with the collaborative efforts for innovative clinical trial

radiotherapy, therapeutics, clinical trials, targeted therapy

Neurofibromatosis

*Mina Lobbous and Bruce R. Korf*

#### **Chapter 6**

## Therapeutic Development in Neurofibromatosis

*Mina Lobbous and Bruce R. Korf*

#### **Abstract**

Although neurofibromatosis (NF) was initially recognized in the nineteenth century, only in the past two decades we have witnessed a paradigm shift in therapeutics. This progress is driven by the increasing understanding of the natural history of the NF-associated tumors and understanding of the molecular landscape of these disorders. Multiple clinical trials have been launched evaluating non-surgical treatment modalities and more studies are in the pipeline. Recently, the NF community has adopted standardized endpoints recommended by the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration established in 2011. Such collaborations among academic, regulatory and supporting communities are crucial for providing the infrastructure needed for advancing the therapeutic development in the field of NF.

**Keywords:** neurofibromatosis type I, neurofibromatosis type II, chemotherapy, radiotherapy, therapeutics, clinical trials, targeted therapy

#### **1. Introduction**

The neurofibromatoses are a heterogenous group of familial tumor predisposition syndromes that result from pathogenic variants in tumor suppressor genes leading to dysregulation in various cellular pathways. This dysregulation eventually leads to tumors of the central and peripheral nervous systems as well as multiorgan involvement. The incidence of Neurofibromatosis type 1 (NF1) is approximately 1 in every 2500–3500 births [1], while the incidence of neurofibromatosis type 2 (NF2) is approximately 1 in every 25,000–33,000 births [2]. Schwannomatosis (SWN) has been identified as a distinct entity with different genetic etiology and clinical phenotype from NF2, but it is difficult to assess the precise incidence of this condition. Although the tumors that develop most frequently in NF1, NF2 and SWN are histologically benign, they can cause significant neurologic disabilities and even mortality due to the involvement of the central and peripheral nervous systems. These tumors represent a unique therapeutic challenge due to the heterogeneity in severity and rate of progression among patients and hence novel therapeutic approaches are needed. In this chapter, we will review the recent studies in the field of neurofibromatosis therapeutics along with the collaborative efforts for innovative clinical trial designs.

#### **2. The power of collaboration in neurofibromatosis research**

The establishment of the NFCTC in 2006 by the Department of Defense was a landmark in the field of NF therapeutics development [3]. The consortium has been in continuous operation since inception. It provides infrastructure, and shared resources across multiple institutions to generate resource-efficient clinical trials. The REiNS working groups are another clear example of the influence of collaboration among NF experts to advance the NF drug development efforts. The Children's Tumor Foundation (CTF) has provided support to the NF community, including efforts to advance research as well as public education and patient support. In 2007, the CTF invested \$4 million to launch the Neurofibromatosis Preclinical Consortium (NFPC) to test candidate drug therapies in NF1 and NF2 models. The Neurofibromatosis Therapeutic Acceleration (NTAP) was established as a private philanthropy to accelerate the development of effective therapeutics for pNFs and cNFs. NTAP has partnered with CTF in the evaluation of potential therapeutic agents in animal models of pNFs.

The collaborative efforts among academic, federal regulatory, and private foundations have resulted in early successes in the NF therapeutic development. In February 2018, selumetinib, a MEK1/2 inhibitor co-developed by AstraZenca and Merck&Co, received breakthrough status from the FDA. Selumetinib was granted Orphan Drug Designation based on data from the phase II trial that tested selumetinib in pediatric patients with inoperable pNFs (NCT01362803) [4] and hence, selumetinib may become the first approved drug for NF. This success highlights the power of collaboration, which moved Selumetinib from a repurposed oncology drug to its current clinical success in NF patients. The funders involved for in this "MEK story" are the CTF, the National Institute of Health (NIH), the Congressionally Directed Medical Research Program (CDMRP) through NFCTC, and the NTAP at Johns Hopkins University [5].

#### **3. Therapeutic development in neurofibromatosis type I**

Understanding of the pathogenesis and molecular landscape of the NF1 associated tumors has advanced dramatically in recent years. This advancement, along with the continued collaborative approaches across the research community, has fueled therapeutic development efforts against many of the NF1 manifestations. Therapeutic development in NF1 has been tumor-specific, due to the substantial heterogeneity of the development and behavior of NF1-associated tumors across and within patients. Plexiform neurofibromas (pNFs), the source of major morbidity in NF1, has been an area of major focus for therapeutic development, followed by other NF1-associated tumors including cutaneous neurofibromas (cNF), optic pathway gliomas (OPG), and malignant peripheral nerve sheath tumors (MPNST).

#### **3.1 NF1-associated plexiform neurofibroma**

Plexiform neurofibromas (pNFs) affect up to 50% of NF1 patients and can involve any peripheral nerve [6, 7]. They occur most commonly in the trunk, followed by the extremities [6]. pNFs tend to grow most rapidly in early childhood and may increase by ≥20% per volume per year in young children [8]. Though surgery remains the mainstay for treatment of pNF, complete resection is virtually impossible due to the frequent involvement of adjacent normal tissue, and occasionally critical structures. Moreover, surgical resection is frequently challenging since pNF can cross tissue planes and involve multiple body regions. The most common

**87**

*Therapeutic Development in Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.89037*

**3.2 NF1-associated gliomas**

NF1-associated pediatric low-grade glioma [39].

that was validated in a recent study [43].

influence future clinical trials in NF1-associated gliomas.

morbidities leading to surgery are neurologic, disfigurement, and airway involvement [9]. A substantial risk of pNF regrowth after surgical resection has motivated

There are multiple ongoing clinical trials (**Table 1**) targeting pNF which represent a rapid expansion in the pNF therapeutic landscape. Though some of the tested drugs have failed to achieve the primary endpoint, they helped establish the natural history of the growth rates of pNF [10, 11]. The therapeutic development efforts in pNFs had shifted from testing "empirically," usually cytotoxic, agents to agents being supported by well-established transitional studies. The first agent that showed radiographic response was imatinib, with a response rate of 17% [12]. Ras-pathway targeted therapy has been of particular interest, as it provides an opportunity for treating multiple manifestations of NF1 with one drug. For example, Selumetinib, which is a MEK (mitogen-activated protein kinase) inhibitor, has shown activity in

the ongoing research to find non-invasive therapies for pNF.

pNF and low-grade gliomas (including OPG) associated with NF1 [13].

Optic pathway glioma (OPG) is the most common form of glioma seen in individuals with NF1. While 15–20% of children with NF1 will develop OPG [27, 28] only 30–50% will be symptomatic and one-third will require therapeutic intervention [29]. In those with confirmed decline in visual acuity (VA) or involvement in the hypothalamus, chemotherapy is the mainstay of treatment. First-line chemotherapeutic agents include vincristine and carboplatin [30], while second-line agents include vinblastine [31], vinorelbine [32], and temozolomide [33]. There is a report of four cases of refractory OPG (two sporadic and two NF1-associated OPG) that showed marked improvement in VA following treatment with bevacizumab [34]. These agents rarely restore the premorbid visual acuity and the aim of treatment is usually to stabilize disease and prevent further worsening [35, 36]. Radiotherapy is usually avoided in NF1-associated OPG for concern of secondary tumors [37] and moya moya syndrome [38] Surgical excision of OPG is not feasible due to the tumor location and is usually reserved for instances of complete loss of vision, severe proptosis, or hydrocephalus. Recently, small molecule inhibitors have been used for refractory OPG in clinical trials (**Table 2**). Among these agents, selumetinib has shown promising results in phase II studies and was proven to be active in recurrent, refractory or progressive

Unnecessary cytotoxic therapies for OPG should be avoided, as many OPGs remain asymptomatic and some even regress over time [28]. One of the efforts to standardize the VA assessment in clinical trials for NF1-associated OPG is through using optic coherence tomography (OCT) [40, 41]. OCT provides an objective assessment of the retinal nerve fiber layer thickness. OCT is a noninvasive tool to monitor children with OPG in whom, especially the youngest ones, traditional methods of VA assessment is challenging [42]. Another objective noninvasive tool to asses VA in NF1-associated OPG is automated tractography of the optic radiation

A retrospective study that analyzed the clinical and pathological features of gliomas in 100 individuals with NF1 emphasized the wide histologic spectrum of gliomas in those with NF1 [44]. Indeed, individuals with NF1 have an increased risk of malignant gliomas compared with the general population [45], but there are confounding reports on glioblastoma prognosis in those with NF1 vs. cases without NF1 [46, 47]. A recent study analyzed the molecular landscape of gliomas in NF1 and showed that 50% of low-grade gliomas displayed an immune signature, T-lymphocytic infiltrate, and increased neoantigen load [48], findings that may

#### *Therapeutic Development in Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.89037*

*Neurofibromatosis - Current Trends and Future Directions*

agents in animal models of pNFs.

and the NTAP at Johns Hopkins University [5].

**3.1 NF1-associated plexiform neurofibroma**

**3. Therapeutic development in neurofibromatosis type I**

**2. The power of collaboration in neurofibromatosis research**

The establishment of the NFCTC in 2006 by the Department of Defense was a landmark in the field of NF therapeutics development [3]. The consortium has been in continuous operation since inception. It provides infrastructure, and shared resources across multiple institutions to generate resource-efficient clinical trials. The REiNS working groups are another clear example of the influence of collaboration among NF experts to advance the NF drug development efforts. The Children's Tumor Foundation (CTF) has provided support to the NF community, including efforts to advance research as well as public education and patient support. In 2007, the CTF invested \$4 million to launch the Neurofibromatosis Preclinical Consortium (NFPC) to test candidate drug therapies in NF1 and NF2 models. The Neurofibromatosis Therapeutic Acceleration (NTAP) was established as a private philanthropy to accelerate the development of effective therapeutics for pNFs and cNFs. NTAP has partnered with CTF in the evaluation of potential therapeutic

The collaborative efforts among academic, federal regulatory, and private foundations have resulted in early successes in the NF therapeutic development. In February 2018, selumetinib, a MEK1/2 inhibitor co-developed by AstraZenca and Merck&Co, received breakthrough status from the FDA. Selumetinib was granted Orphan Drug Designation based on data from the phase II trial that tested selumetinib in pediatric patients with inoperable pNFs (NCT01362803) [4] and hence, selumetinib may become the first approved drug for NF. This success

highlights the power of collaboration, which moved Selumetinib from a repurposed oncology drug to its current clinical success in NF patients. The funders involved for in this "MEK story" are the CTF, the National Institute of Health (NIH), the Congressionally Directed Medical Research Program (CDMRP) through NFCTC,

Understanding of the pathogenesis and molecular landscape of the NF1 associated tumors has advanced dramatically in recent years. This advancement, along with the continued collaborative approaches across the research community, has fueled therapeutic development efforts against many of the NF1 manifestations. Therapeutic development in NF1 has been tumor-specific, due to the substantial heterogeneity of the development and behavior of NF1-associated tumors across and within patients. Plexiform neurofibromas (pNFs), the source of major morbidity in NF1, has been an area of major focus for therapeutic development, followed by other NF1-associated tumors including cutaneous neurofibromas (cNF), optic pathway gliomas (OPG), and malignant peripheral nerve sheath tumors (MPNST).

Plexiform neurofibromas (pNFs) affect up to 50% of NF1 patients and can involve any peripheral nerve [6, 7]. They occur most commonly in the trunk, followed by the extremities [6]. pNFs tend to grow most rapidly in early childhood and may increase by ≥20% per volume per year in young children [8]. Though surgery remains the mainstay for treatment of pNF, complete resection is virtually impossible due to the frequent involvement of adjacent normal tissue, and occasionally critical structures. Moreover, surgical resection is frequently challenging since pNF can cross tissue planes and involve multiple body regions. The most common

**86**

morbidities leading to surgery are neurologic, disfigurement, and airway involvement [9]. A substantial risk of pNF regrowth after surgical resection has motivated the ongoing research to find non-invasive therapies for pNF.

There are multiple ongoing clinical trials (**Table 1**) targeting pNF which represent a rapid expansion in the pNF therapeutic landscape. Though some of the tested drugs have failed to achieve the primary endpoint, they helped establish the natural history of the growth rates of pNF [10, 11]. The therapeutic development efforts in pNFs had shifted from testing "empirically," usually cytotoxic, agents to agents being supported by well-established transitional studies. The first agent that showed radiographic response was imatinib, with a response rate of 17% [12]. Ras-pathway targeted therapy has been of particular interest, as it provides an opportunity for treating multiple manifestations of NF1 with one drug. For example, Selumetinib, which is a MEK (mitogen-activated protein kinase) inhibitor, has shown activity in pNF and low-grade gliomas (including OPG) associated with NF1 [13].

#### **3.2 NF1-associated gliomas**

Optic pathway glioma (OPG) is the most common form of glioma seen in individuals with NF1. While 15–20% of children with NF1 will develop OPG [27, 28] only 30–50% will be symptomatic and one-third will require therapeutic intervention [29]. In those with confirmed decline in visual acuity (VA) or involvement in the hypothalamus, chemotherapy is the mainstay of treatment. First-line chemotherapeutic agents include vincristine and carboplatin [30], while second-line agents include vinblastine [31], vinorelbine [32], and temozolomide [33]. There is a report of four cases of refractory OPG (two sporadic and two NF1-associated OPG) that showed marked improvement in VA following treatment with bevacizumab [34]. These agents rarely restore the premorbid visual acuity and the aim of treatment is usually to stabilize disease and prevent further worsening [35, 36]. Radiotherapy is usually avoided in NF1-associated OPG for concern of secondary tumors [37] and moya moya syndrome [38] Surgical excision of OPG is not feasible due to the tumor location and is usually reserved for instances of complete loss of vision, severe proptosis, or hydrocephalus.

Recently, small molecule inhibitors have been used for refractory OPG in clinical trials (**Table 2**). Among these agents, selumetinib has shown promising results in phase II studies and was proven to be active in recurrent, refractory or progressive NF1-associated pediatric low-grade glioma [39].

Unnecessary cytotoxic therapies for OPG should be avoided, as many OPGs remain asymptomatic and some even regress over time [28]. One of the efforts to standardize the VA assessment in clinical trials for NF1-associated OPG is through using optic coherence tomography (OCT) [40, 41]. OCT provides an objective assessment of the retinal nerve fiber layer thickness. OCT is a noninvasive tool to monitor children with OPG in whom, especially the youngest ones, traditional methods of VA assessment is challenging [42]. Another objective noninvasive tool to asses VA in NF1-associated OPG is automated tractography of the optic radiation that was validated in a recent study [43].

A retrospective study that analyzed the clinical and pathological features of gliomas in 100 individuals with NF1 emphasized the wide histologic spectrum of gliomas in those with NF1 [44]. Indeed, individuals with NF1 have an increased risk of malignant gliomas compared with the general population [45], but there are confounding reports on glioblastoma prognosis in those with NF1 vs. cases without NF1 [46, 47]. A recent study analyzed the molecular landscape of gliomas in NF1 and showed that 50% of low-grade gliomas displayed an immune signature, T-lymphocytic infiltrate, and increased neoantigen load [48], findings that may influence future clinical trials in NF1-associated gliomas.


**89**

**Drug** Sunitinib NCT01402817 Pexidartinib [24]

NCT02390752 Cabozantinib NCT02101736 Trametinib NCT02124772 PD-0325901 [25]

NCT02096471 Selumetinib [26]

NCT01362803 Selumetinib NCT02407405

Binimetinib

NCT03231306

Selumetinib (intermittent dosing)

NCT03326388

Trametinib

NCT03363217

Imatinib (in pNF with airway

involvement)

NCT03688568

**Target** PDGFR, VEGFR, c-kit

c-kit, FLT3, CSF1R

RET, c-MET, VEGFR

MEK MEK MEK MEK MEK MEK MEK c-kit, PDGFR

II

6 months–12 years

*Abbreviations: 3D ORR, volumetric objective radiographic response; BCR-ABL, fusion gene of breakpoint cluster region and Abl1; c-kit, kit ligand or stem cell factor; c-MET, MET proton-oncogene; CSF1R,* 

*colony stimulating factor 1 receptor; FLT3, Fms-like tyrosine kinase 11; MEK, mitogen activated protein kinas; mTOR, mammalian target of rapamycin; PD, pharmacodynamic; PDGFR platelet-derived* 

*growth factor; PFT, pulmonary function test; PK, pharmacokinetics; RECIST, Response Evaluation Criteria In Solid Tumors; RET, rearranged during transfection proto-oncogene; TTP, time to progression;* 

*VEGFR vascular endothelial growth factor receptor; ORR, objective response rate.*

*Clinical trials for neurofibromatosis type 1-associated plexiform neurofibromas.*

**Table 1.**

Sleep study/PFT, 3D

ORR

II

1 month–25 years

3D ORR, TTP RECIST

Recruiting

Recruiting

I, II

3–18

Toxicity, 3D ORR

II

≥1

3D ORR

II

≥18

3D ORR

I, II

2–18

3D ORR

II

≥16

3D ORR

I

1 month–17 years

PK, PD, toxicity

II

≥3

3D ORR

I, II

3–31

ORR

II

3–65

**Phase**

**Age (y)**

**Endpoints**

3D ORR

**Results** Terminated (1 patient died)

Recruiting Recruiting Recruiting Completed, 42% 3D ORR

Active, not recruiting, 71% 3D ORR

Recruiting

Recruiting

Active, not recruiting

*Therapeutic Development in Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.89037*

#### *Neurofibromatosis - Current Trends and Future Directions*


#### *Therapeutic Development in Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.89037*

*Neurofibromatosis - Current Trends and Future Directions*

**88**

**Drug** Thalidomide [14]

Sirolimus [15]

NCT00634270

Sorafenib [16]

NCT00727233

Pirfenidone [17, 18]

NCT00076102

Cediranib

NCT00326872

Tipifarnib [19]

NCT00021541

PEG-Interferon alpha 2b [20, 21]

Immune, angiogenesis

Cytotoxic

II

≤25

TTP

I, II

18 months–21 years in

TTP, 3D ORR

phase II

NCT00396019

Vinblastine/Methotrexate

NCT00030264

Celecoxib; PEG-Interferon alpha

Immune, angiogenesis

II

2–30

Symptoms improvement,

ORR

2b

NCT00846430

Nilotinib

BCR-ABL, PDGFR, c-kit

mTOR mTOR c-kit, PDGFR

II

3–65

RECIST, 3D ORR

II

>10

3D ORR, TTP

II

18–60

3D ORR

Pilot

≥18

RECIST,3D ORR

Completed

Completed, no objective response

Terminated due to slow accrual

17% 3D ORR

NCT01275586

Everolimus [22]

NCT01412892

Everolimus

NCT01365468

Imatinib [23]

NCT01673009

**Target** Angiogenesis

mTOR Raf kinase, c-kit, PDGF,

I

3–18

3D ORR

VEGFR2,3

Fibroblast proliferation

VEGFR-1, -2, -3

Farnesyl transferase

I, II

3–25

TTP, 3D ORR

II

≥18

3D ORR

I, II

3–21

3D ORR

II

>3

**Phase**

I

>5

**Age (y)**

**Endpoints**

ORR 3D ORR, TTP

**Results**

Completed/unclear benefit

Modest increase in TTP, no objective response

Intolerable, decrease in QOL due to pain, no

objective response

Completed, no objective response

Terminated due to slow accrual

Completed, No difference in TTP

Doubled TTP, 3D ORR less than 20%

Completed, pending results

Active, not recruiting

*Abbreviations: 3D ORR, volumetric objective radiographic response; BCR-ABL, fusion gene of breakpoint cluster region and Abl1; c-kit, kit ligand or stem cell factor; c-MET, MET proton-oncogene; CSF1R, colony stimulating factor 1 receptor; FLT3, Fms-like tyrosine kinase 11; MEK, mitogen activated protein kinas; mTOR, mammalian target of rapamycin; PD, pharmacodynamic; PDGFR platelet-derived growth factor; PFT, pulmonary function test; PK, pharmacokinetics; RECIST, Response Evaluation Criteria In Solid Tumors; RET, rearranged during transfection proto-oncogene; TTP, time to progression; VEGFR vascular endothelial growth factor receptor; ORR, objective response rate.*

#### **Table 1.**

*Clinical trials for neurofibromatosis type 1-associated plexiform neurofibromas.*


*Abbreviations: MEK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor.*

#### **Table 2.**

*Clinical trials for optic pathway gliomas (OPG) and other gliomas associated with neurofibromatosis type 1.*

#### **3.3 NF1-associated malignant peripheral nerve sheath tumors**

Malignant peripheral nerve sheath tumors (MPNSTs) are rare high-grade sarcomas with poor prognosis [49]. MPNSTs occur more frequently in those with NF1 compared with the general population, with a lifetime risk of 8–13% [50]. Several studies have not shown a significant difference in the molecular landscape between sporadic and NF1-associated MPNSTs [51, 52]. FDG-PET remains the gold standard noninvasive diagnostic tool for MPNSTs, with 89–100% sensitivity and 72–95 specificity [53, 54]. Surgical resection with negative margins is the mainstay of treatment [55], though that is not usually feasible. Use of adjuvant radiotherapy to induce local control in MPSNTs failed to show improvement in overall survival in NF1-associated MPNSTs [56].

There are limited chemotherapeutic options, including agents like doxorubicin, and ifosfamide [57, 58]. A phase II study of bevacizumab and everolimus that enrolled 25 individuals (17 had NF1-associated MPNST) did not show a clinical benefit (defined as complete response, partial response or stable disease for ≥4 months) [59]. Although preclinical studies showed EGFR amplification in MPSNT [60], EGFR inhibitors did not show clinical activity against MPNST in clinical trials. A few studies have been conducted in sarcomas using targeted therapy, and these have not shown clinical activity; tested drugs included imatinib [61], dasatinib [62], sorafenib [63], and erlotinib [64]. These negative studies emphasize the importance of developing xenografts to explore new therapeutic targets and explore pathways of interest like the NF1/P53-mutant transgenic MPNST model [65–67].

**91**

**Table 3.**

*Therapeutic Development in Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.89037*

**3.4 NF1-associated cutaneous neurofibromas**

**Drug Target Phase Age** 

MEK and mTOR

Oncolytic virotherapy

PDGFR, VEGFR, c-kit (Pazopanib), TORC1&2 (Sapanisertib)

c-kit, FLT3, CSF1R, mTOR

*endothelial growth factor receptor; ORR, objective response rate.*

EGFR806 CAR-T

Selumetinib and Sirolimus NCT03433183

Injectable MVEdm vaccine strain NCT02700230

Pazopanib vs. Sapanisertib NCT02601209

Lorvotuzumab mertansine NCT02452554

Pexidartinib and Sirolimus NCT02584647

cell NCT03618381

Combined targeted therapy has been used to exploit cellular vulnerabilities of cancer cells, as in RAS-driven tumors which are refractory to conventional therapies. A preclinical study has shown dramatic tumor shrinkage in a transgenic MPNST mouse model in response to combined HSP90 and mTOR inhibition [68]. This promising preclinical work had led to a phase I/II study of gantespib, a novel injectable inhibitor of HSP90 and the mTOR inhibitor, sirolimus. The study enrolled 20 participants (NCT02008877) and results are pending [69]. Another novel approach undergoing phase I study utilizes the oncolytic potential of the genetically engineered injectable measles virus Edmonston vaccine strain (MVEdm) that encodes thyroid sodium iodide symporter [70] (**Table 3**).

Cutaneous neurofibromas (cNFs) are among the most common manifestations in NF1, affecting about 99% of patients with NF1 [71]. cNFs are unlikely to undergo malignant transformation or to cause fatal complications or severe neurologic disability. Nevertheless, cNFs are considered one of the greatest concerns in patients, especially adults, with NF1. These concerns are mainly due to disfigurement and dysesthesia, causing substantial psychological distress and negative body image perception [72]. There is immense variability in cNF among patients with NF1 with respect to size, location, age at first presentation, associated symptoms, and number. These factors affect the therapeutic approach to cNFs and emphasize the need for reproducible and reliable endpoints to ensure clinical success for tested agents.

> I (Sapanisertib), II

*Abbreviations: CBR, clinical benefit rate; c-kit, kit ligand or stem cell factor; c-MET, MET proton-oncogene; CSF1R, colony stimulating factor 1 receptor; FLT3, Fms-like tyrosine kinase 11; MEK, mitogen activated protein kinas; MTD, maximum tolerated dose; MVEdm; measles virus edmonston vaccine strain, OS, overall survival; PDGFR platelet-derived growth factor; PFS, progression free survival; RECIST, Response Evaluation Criteria In Solid Tumors; TORC, mammalian target of rapamycin complex; TTP, time to progression; VEGFR vascular* 

*Clinical trials for malignant peripheral nerve sheath tumors in neurofibromatosis type 1.*

**(years)**

II ≥12 CBR, PFS,

I ≥18 Toxicity,

Immunotherapy I 1–26 Toxicity Recruiting

CD-56 antibody II 1–30 RECIST Active, not

**Endpoints Status**

Active, not recruiting

Recruiting

Active, not recruiting

recruiting

OS

MTD, ORR

≥18 MTD, PFS, ORR

II ≥18 PFS, OS Recruiting

*Therapeutic Development in Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.89037*

*Neurofibromatosis - Current Trends and Future Directions*

Tumor

microenvironment

Angiogenesis/ immunomodulation

Angiogenesis/ immunomodulation

Vinblastine +/− Bevacizumab NCT02840409

Pegylated interferon NCT02343224

Pomalidomide NCT02415153

Lenalidomide NCT01553149

Everolimus (RAD0001) NCT01158651

Binimetinib (MEK162) NCT02285439

Binimetinib (MEK162) NCT01885195

Selumetinib NCT01089101

**Table 2.**

*endothelial growth factor.*

**Drug Target Phase Age Endpoints Status**

Cytotoxic/VEGF II 6 months–18 years Response

MEK I/II 1–18 years MTD,

MEK II Older than

rate, OS, PFS, visual outcome measures, OCT

MTD

response rate

Response rate

Response rate Completed

II 3–18 years Response rate Recruiting

II 0–21 years Response rate Active, not

I 3–20 years Toxicity,

mTOR II 1–21 years Response rate Active, not

18 years

MEK I/II 3–21 years Safety, MTD,

*Abbreviations: MEK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; VEGF, vascular* 

*Clinical trials for optic pathway gliomas (OPG) and other gliomas associated with neurofibromatosis type 1.*

Recruiting

Active, not recruiting

recruiting

recruiting

Recruiting

(pending results)

Recruiting

**3.3 NF1-associated malignant peripheral nerve sheath tumors**

Malignant peripheral nerve sheath tumors (MPNSTs) are rare high-grade sarcomas with poor prognosis [49]. MPNSTs occur more frequently in those with NF1 compared with the general population, with a lifetime risk of 8–13% [50]. Several studies have not shown a significant difference in the molecular landscape between sporadic and NF1-associated MPNSTs [51, 52]. FDG-PET remains the gold standard noninvasive diagnostic tool for MPNSTs, with 89–100% sensitivity and 72–95 specificity [53, 54]. Surgical resection with negative margins is the mainstay of treatment [55], though that is not usually feasible. Use of adjuvant radiotherapy to induce local control in MPSNTs failed to show improvement in overall survival in

There are limited chemotherapeutic options, including agents like doxorubicin,

and ifosfamide [57, 58]. A phase II study of bevacizumab and everolimus that enrolled 25 individuals (17 had NF1-associated MPNST) did not show a clinical benefit (defined as complete response, partial response or stable disease for ≥4 months) [59]. Although preclinical studies showed EGFR amplification in MPSNT [60], EGFR inhibitors did not show clinical activity against MPNST in clinical trials. A few studies have been conducted in sarcomas using targeted therapy, and these have not shown clinical activity; tested drugs included imatinib [61], dasatinib [62], sorafenib [63], and erlotinib [64]. These negative studies emphasize the importance of developing xenografts to explore new therapeutic targets and explore pathways

of interest like the NF1/P53-mutant transgenic MPNST model [65–67].

**90**

NF1-associated MPNSTs [56].

Combined targeted therapy has been used to exploit cellular vulnerabilities of cancer cells, as in RAS-driven tumors which are refractory to conventional therapies. A preclinical study has shown dramatic tumor shrinkage in a transgenic MPNST mouse model in response to combined HSP90 and mTOR inhibition [68]. This promising preclinical work had led to a phase I/II study of gantespib, a novel injectable inhibitor of HSP90 and the mTOR inhibitor, sirolimus. The study enrolled 20 participants (NCT02008877) and results are pending [69]. Another novel approach undergoing phase I study utilizes the oncolytic potential of the genetically engineered injectable measles virus Edmonston vaccine strain (MVEdm) that encodes thyroid sodium iodide symporter [70] (**Table 3**).

#### **3.4 NF1-associated cutaneous neurofibromas**

Cutaneous neurofibromas (cNFs) are among the most common manifestations in NF1, affecting about 99% of patients with NF1 [71]. cNFs are unlikely to undergo malignant transformation or to cause fatal complications or severe neurologic disability. Nevertheless, cNFs are considered one of the greatest concerns in patients, especially adults, with NF1. These concerns are mainly due to disfigurement and dysesthesia, causing substantial psychological distress and negative body image perception [72]. There is immense variability in cNF among patients with NF1 with respect to size, location, age at first presentation, associated symptoms, and number. These factors affect the therapeutic approach to cNFs and emphasize the need for reproducible and reliable endpoints to ensure clinical success for tested agents.


*Abbreviations: CBR, clinical benefit rate; c-kit, kit ligand or stem cell factor; c-MET, MET proton-oncogene; CSF1R, colony stimulating factor 1 receptor; FLT3, Fms-like tyrosine kinase 11; MEK, mitogen activated protein kinas; MTD, maximum tolerated dose; MVEdm; measles virus edmonston vaccine strain, OS, overall survival; PDGFR platelet-derived growth factor; PFS, progression free survival; RECIST, Response Evaluation Criteria In Solid Tumors; TORC, mammalian target of rapamycin complex; TTP, time to progression; VEGFR vascular endothelial growth factor receptor; ORR, objective response rate.*

#### **Table 3.**

*Clinical trials for malignant peripheral nerve sheath tumors in neurofibromatosis type 1.*

Clinical management for cNF involves surveillance or procedure-based therapy. Conventional surgical resection promotes complete removal of the lesion, but there are obstacles, including limited number of lesions that can be treated in a single session and the scarring that may be induced by surgical resection. Other alternatives include electrodessication, which remove cNFs through dehydration and denaturation [73]. This allows for removal of large numbers (up to thousands) of cNFs in one session, but it requires general anesthesia and may cause scarring and pigmentation changes. A retrospective study of 106 individuals with multiple, small cNFs treated with CO2 laser ablation reported >90% patient satisfaction, yet a local infection rate was reported to be 15% [74]. Other procedure-based therapies reported in cNFs are laser photocoagulation [75] and radiofrequency ablation [76]. Another approach using local drug/device combinations is the photodynamic therapy (PDT), which is being tested in different cancers [77]. PDT in cNFs studies use a photosensitizer, 5-amino-levulinic acid, plus illumination with red light. PDT was evaluated in phase I study (NCT01682811) and a phase II study (NCT02728388) is active in a single US institution.

One of the early efforts for treatment of cNFs and their associated symptoms used ketotifen [78]. Ketotifen is a histamine 1 receptor blocker which facilitates mast cell stabilization and; its use in NF1 is based on the finding of abundant mast cells in neurofibromas. Improvement in pain and pruritis has been reported, but objective tumor shrinkage has not been documented. Three drugs have been tested in cNFs using local therapeutic approaches; the first was ranibizumab, a vascular endothelial growth factor monoclonal antibody, which was injected intralesionally (NCT00657202). The overall effect of the treatment was minimal and the variability in the tumor volume assessment (measured by a caliper) limited the interpretation of the data. The second agent was topical imiquimod, which showed minimal efficacy in tumor shrinkage compared to baseline volume (measured by a caliper) (NCT00865644). The third agent was topical rapamycin, an mTOR inhibitor, which was initially tested in Tuberous Sclerosis Complex (TSC)-associated angiofibromas (NCT01031901) [79]. The study enrolled 52 patients with TSC and NF1 and data are expected.

Due to the relatively benign histology of cNFs and the likely need for long term therapy, there are special considerations pertaining to cNF drug development [80]. The safety profile of tested drugs is a major concern to physicians, regulators, patients and their caregiver. Also, the route of administration and cost are important considerations, as individuals with cNF are more likely to require treatment (either medication or intervention) for an extended period of time. The variant phenotype among affected persons, demographic differences, and the goal of treatment are important factor determining the type and timing of treatment.

The above-mentioned considerations, especially the safety profile, make oral systemic therapies preferable for individuals with a heavy tumor burden. Everolimus, an oral mTOR inhibitor, was evaluated in a phase II study of disfiguring cNF associated with NF1 (NCT02334902). The study enrolled 22 patients and used photographic measurement of selected lesion to assess surface volume. While 5/22 patients withdrew due to adverse events, a very modest effect was reported in <20% of the participants [81]. Due to the promising results of using targeted therapied against MEK, selumetinib is being studied in NF1-associated cNFs (NCT02839720). The study is a phase II, multi-institutional, open label study with the primary outcome measure being the change in the size of cNFs assessed by digital photography and caliper measurements.

The Clinical Trial Design and Development REiNS subgroup, involving experts from different settings, has presented the priorities and challenges associated with conducting clinical trials targeting cNF in NF1 [82]. The subgroup members

**93**

*Therapeutic Development in Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.89037*

reviewed key topics like natural history, assessment methods, functional endpoints, safety, and development strategies. One of the most important topics, which pose a major challenge in cNF clinical trials, is the measurement of outcomes. Methods of measurement that have been used include calipers, digital and volume photography, ultrasound, and MRI. The subgroup members support considering clinically meaningful measures of effectiveness in interpreting changes in tumor size or number. Tumor size reduction that correlates with improved pain control or discomfort is more clinically meaningful than the crude number or size of the tumors. New approaches, such as high-frequency ultrasound or optical coherence tomography, may be able to address some of the limitations of the conventional methods like MRI, photography or caliper measurement. These new approaches need to be validated through additional studies. The subgroup members recommend several key factors when designing clinical trials on cNF, including timing to initiate intervention, eligibility criteria to ensure diversity, mechanism of the intervention, route of

administration, safety monitoring, and regulatory considerations.

**4. Therapeutic development in neurofibromatosis type 2**

peutic pathway between NF2-associated VS and sporadic VS [91].

they may lead to a shortened life expectancy [89].

NF2 is an autosomal dominant disorder that affects the central and peripheral nervous systems. NF2 has an estimated incidence of 1 in 25,000–33,000 births, making it far less common than NF1 [83]. Vestibular schwannomas (VS) are considered the hallmark of NF2, and bilateral VS fulfill the clinical diagnosis of definite NF2 [84]. The average age at diagnosis in NF2-associated VS is about 27 years [85]; diagnosis in childhood predicts a severe phenotype and unfavorable prognosis [86]. Though VS are slowly progressive tumors, they can cause significant neurologic disability, including hearing loss and eventually deafness, balance problems, and brain stem compression [87]. The other common tumor associated with NF2 is meningioma, which is the most common intracranial tumor worldwide. Up to half of individuals with NF2 develop meningiomas [88], and despite benign histology,

The loss of the tumor suppressor protein merlin in NF2 leads to activation of prosurvival pathways via RAS modulation. Hence, NF2 shares many of the same targets identified in NF1. Merlin is absent not only in NF2-associated VS, but also in sporadic VS [90]. This observation is important as it may point to a shared thera-

Though surgery remains the mainstay of treatment in sporadic VS, or stereotactic radiosurgery (SRS) for tumors <3 cm [92], these approaches have proved to be less efficacious in NF2-associated VS, with high rate of complications, including facial nerve weakness, hearing loss, and headache [93, 94]. Moreover, there are growing concerns about utilizing radiation therapy in NF2 due to risk of late malignant transformation [95]. Some of the challenges that face NF2 clinical trials are the substantial variability in disease severity across individuals with NF2, the lack of clear association between the rate of VS growth and the rate of hearing loss, and the variable growth rates between the right and the left VS in same patient [96]. A prospective study that highlighted the lack of correlation between VS size or growth rate and rate of hearing loss was published in 2014 and included 120 individuals with NF2-associated VS (total of 200 VS) [97]. The investigators used word recognition score (WRS) as an objective measurement for hearing decline and defined radiographic tumor growth as ≥20% increase in tumor volume compared with baseline. The study showed that the mean rate of hearing decline from diagnosis was 5% at 1 year and 16% at 3 years, while the rate of VS tumor graphic progression was 31% at 1 year and 79% at 3 years. The median time to progression

#### *Therapeutic Development in Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.89037*

*Neurofibromatosis - Current Trends and Future Directions*

active in a single US institution.

Clinical management for cNF involves surveillance or procedure-based therapy.

One of the early efforts for treatment of cNFs and their associated symptoms used ketotifen [78]. Ketotifen is a histamine 1 receptor blocker which facilitates mast cell stabilization and; its use in NF1 is based on the finding of abundant mast cells in neurofibromas. Improvement in pain and pruritis has been reported, but objective tumor shrinkage has not been documented. Three drugs have been tested in cNFs using local therapeutic approaches; the first was ranibizumab, a vascular endothelial growth factor monoclonal antibody, which was injected intralesionally (NCT00657202). The overall effect of the treatment was minimal and the variability in the tumor volume assessment (measured by a caliper) limited the interpretation of the data. The second agent was topical imiquimod, which showed minimal efficacy in tumor shrinkage compared to baseline volume (measured by a caliper) (NCT00865644). The third agent was topical rapamycin, an mTOR inhibitor, which was initially tested in Tuberous Sclerosis Complex (TSC)-associated angiofibromas (NCT01031901) [79]. The study enrolled 52 patients with TSC and NF1 and data are

Due to the relatively benign histology of cNFs and the likely need for long term

The Clinical Trial Design and Development REiNS subgroup, involving experts

from different settings, has presented the priorities and challenges associated with conducting clinical trials targeting cNF in NF1 [82]. The subgroup members

therapy, there are special considerations pertaining to cNF drug development [80]. The safety profile of tested drugs is a major concern to physicians, regulators, patients and their caregiver. Also, the route of administration and cost are important considerations, as individuals with cNF are more likely to require treatment (either medication or intervention) for an extended period of time. The variant phenotype among affected persons, demographic differences, and the goal of treat-

ment are important factor determining the type and timing of treatment. The above-mentioned considerations, especially the safety profile, make oral systemic therapies preferable for individuals with a heavy tumor burden. Everolimus, an oral mTOR inhibitor, was evaluated in a phase II study of disfiguring cNF associated with NF1 (NCT02334902). The study enrolled 22 patients and used photographic measurement of selected lesion to assess surface volume. While 5/22 patients withdrew due to adverse events, a very modest effect was reported in <20% of the participants [81]. Due to the promising results of using targeted therapied against MEK, selumetinib is being studied in NF1-associated cNFs (NCT02839720). The study is a phase II, multi-institutional, open label study with the primary outcome measure being the change in the size of cNFs assessed by

digital photography and caliper measurements.

Conventional surgical resection promotes complete removal of the lesion, but there are obstacles, including limited number of lesions that can be treated in a single session and the scarring that may be induced by surgical resection. Other alternatives include electrodessication, which remove cNFs through dehydration and denaturation [73]. This allows for removal of large numbers (up to thousands) of cNFs in one session, but it requires general anesthesia and may cause scarring and pigmentation changes. A retrospective study of 106 individuals with multiple, small cNFs treated with CO2 laser ablation reported >90% patient satisfaction, yet a local infection rate was reported to be 15% [74]. Other procedure-based therapies reported in cNFs are laser photocoagulation [75] and radiofrequency ablation [76]. Another approach using local drug/device combinations is the photodynamic therapy (PDT), which is being tested in different cancers [77]. PDT in cNFs studies use a photosensitizer, 5-amino-levulinic acid, plus illumination with red light. PDT was evaluated in phase I study (NCT01682811) and a phase II study (NCT02728388) is

**92**

expected.

reviewed key topics like natural history, assessment methods, functional endpoints, safety, and development strategies. One of the most important topics, which pose a major challenge in cNF clinical trials, is the measurement of outcomes. Methods of measurement that have been used include calipers, digital and volume photography, ultrasound, and MRI. The subgroup members support considering clinically meaningful measures of effectiveness in interpreting changes in tumor size or number. Tumor size reduction that correlates with improved pain control or discomfort is more clinically meaningful than the crude number or size of the tumors. New approaches, such as high-frequency ultrasound or optical coherence tomography, may be able to address some of the limitations of the conventional methods like MRI, photography or caliper measurement. These new approaches need to be validated through additional studies. The subgroup members recommend several key factors when designing clinical trials on cNF, including timing to initiate intervention, eligibility criteria to ensure diversity, mechanism of the intervention, route of administration, safety monitoring, and regulatory considerations.

#### **4. Therapeutic development in neurofibromatosis type 2**

NF2 is an autosomal dominant disorder that affects the central and peripheral nervous systems. NF2 has an estimated incidence of 1 in 25,000–33,000 births, making it far less common than NF1 [83]. Vestibular schwannomas (VS) are considered the hallmark of NF2, and bilateral VS fulfill the clinical diagnosis of definite NF2 [84]. The average age at diagnosis in NF2-associated VS is about 27 years [85]; diagnosis in childhood predicts a severe phenotype and unfavorable prognosis [86]. Though VS are slowly progressive tumors, they can cause significant neurologic disability, including hearing loss and eventually deafness, balance problems, and brain stem compression [87]. The other common tumor associated with NF2 is meningioma, which is the most common intracranial tumor worldwide. Up to half of individuals with NF2 develop meningiomas [88], and despite benign histology, they may lead to a shortened life expectancy [89].

The loss of the tumor suppressor protein merlin in NF2 leads to activation of prosurvival pathways via RAS modulation. Hence, NF2 shares many of the same targets identified in NF1. Merlin is absent not only in NF2-associated VS, but also in sporadic VS [90]. This observation is important as it may point to a shared therapeutic pathway between NF2-associated VS and sporadic VS [91].

Though surgery remains the mainstay of treatment in sporadic VS, or stereotactic radiosurgery (SRS) for tumors <3 cm [92], these approaches have proved to be less efficacious in NF2-associated VS, with high rate of complications, including facial nerve weakness, hearing loss, and headache [93, 94]. Moreover, there are growing concerns about utilizing radiation therapy in NF2 due to risk of late malignant transformation [95]. Some of the challenges that face NF2 clinical trials are the substantial variability in disease severity across individuals with NF2, the lack of clear association between the rate of VS growth and the rate of hearing loss, and the variable growth rates between the right and the left VS in same patient [96]. A prospective study that highlighted the lack of correlation between VS size or growth rate and rate of hearing loss was published in 2014 and included 120 individuals with NF2-associated VS (total of 200 VS) [97]. The investigators used word recognition score (WRS) as an objective measurement for hearing decline and defined radiographic tumor growth as ≥20% increase in tumor volume compared with baseline. The study showed that the mean rate of hearing decline from diagnosis was 5% at 1 year and 16% at 3 years, while the rate of VS tumor graphic progression was 31% at 1 year and 79% at 3 years. The median time to progression

(14 months) was significantly shorter than the median time to hearing decline (62 months) [93]. This study, along with prior reports, elucidated the natural history of individuals with NF2 to help to determine the most appropriate timing for intervention [81, 83, 98].

Clinical trials for NF2 have been focused on vestibular schwannomas, since loss of hearing is often the most pressing concern in individuals with NF2. A group of 36 international researchers, physicians, representatives from the pharmaceutical industry, and patient advocates held a workshop to provide consensus recommendations to accelerate clinical trials progress in NF2 [99]. The group provided recommendations on participant selection, clinically meaningful and feasible endpoints, the clinical trials models most appropriate for NF2, and candidate therapeutic agents for NF2.

Different cellular pathways have been targeted in clinical trials for NF2 associated tumors (**Table 4**), with mixed responses. One of the most promising agents used in NF2 is bevacizumab, which was initially given on a compassionate use basis for adults with NF2-associated VS with severe disability [100, 101]. In these reports, 6 of 10 participants had ≥20% reduction in tumor volume and significantly improved hearing. The promising results led to designing two phase II clinical trials using bevacizumab in persons with NF2 who suffered from progressive hearing loss. A preliminary report from one of these 2 trials that enrolled 22 participants showed that the overall hearing and radiographic response rates were 41 and 23% respectively, though pediatric participants appeared to benefit less compared to adults (NCT01767792) [102]. Bevacizumab was used in a dose of 10 mg/kg every 2 weeks for 6 months, followed by 5 mg/kg every 3 weeks for 18 months; this regimen was well tolerated.


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AR-42 NCT02104323

Bevacizumab [107] NCT01207687

Bevacizumab [102] NCT01767792

Acetylsalicylic acid NCT03079999

Vistusertib (AZD2014) NCT02831257

Selumetinib NCT03095248

**Table 4.**

**Drug Target Phase Age** 

Antiplatelet, antiinflammatory

> mTORC1, mTORC2

*vestibular schwannoma; WRS, word recognition score.*

**(years)**

II ≥18 MEN: RR using

HDAC Early phase I ≥18 VS and MEN:

VEGF II ≥12 VS: hearing

VEGF II ≥12 VS: hearing

MEK II 3–45 VS, MEN, and

II, randomized, placebocontrol

**Endpoints Status**

Active, not recruiting

Completed, hearing response 36%

Active, not recruiting, hearing response 41%, RR 23%

> Active, not recruiting

> > Active

tumor PK, molecular analysis

response measured by WRS

response measured by WRS

≥12 VS: PFS Active

volumetric MRI

ependymoma: hearing response measured by WRS, RR

NF2 shares many of the same targets identified in NF1; hence, some of the therapeutic agents tested in NF1 are being tested in NF2, including everolimus (NCT01345136), sorafenib, and selumetinib (NCT03095248). The dual mTROC1 and mTORC2 inhibitor, vistusertib (AZD2014), is used in a phase II study for NF2 patients with progressive or symptomatic meningiomas (NCT02831257). While the primary outcome for this study is the radiographic response rate for meningioma using volumetric MRI scans, the secondary outcomes include response assessment for VS and non-target meningioma using volumetric MRI. The NFCTC has approved using crizotinib, a MET and ALK inhibitor, in a phase II study for children and adults with NF2 associated progressive VS. There are promising preclinical studies identifying crizotinib as a potent inhibitor of NF2-null Schwann cell proliferation in vitro and tumor growth in vivo [103]. The goal for these clinical trials is to assess the hearing response rate as a clinically meaningful endpoint and to assess tolerability and long term effects of the

*Clinical trials in Neurofibromatosis type 2-associated vestibular schwannomas and meningiomas.*

*Abbreviations: c-kit, kit ligand or stem cell factor; EGFR/ErBb2, epidermal growth factor reception; HDAC, histone deacetylase; MEK, mitogen activated protein kinas; MEN, meningioma; mTOR, mammalian target of rapamycin; mTORC, mammalian target of rapamycin complex; PDGFR platelet-derived growth factor; PFS, progressionfree survival; PK, pharmacokinetics; VEGF, vascular endothelial growth factor; RR, radiographic response; VS.* 

tested agents, as well as identify biomarkers that can predict outcomes.

Schwannomatosis (SWN), as the name implies, is characterized by the development of multiple peripheral nerve schwannomas, without concomitant involvement

**5. Therapeutic development in Schwannomatosis**

*Therapeutic Development in Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.89037*

*Neurofibromatosis - Current Trends and Future Directions*

18 months; this regimen was well tolerated.

**Drug Target Phase Age** 

VEGF, c-kit, PDGFR

Antiangiogenic

intervention [81, 83, 98].

agents for NF2.

Everolimus [104] NCT01419639

Everolimus [105] NCT01490476

Everolimus NCT01345136

Everolimus NCT01880749

Lapatinib [106] NCT00973739

Lapatinib NCT00863122

Axitinib NCT02129647

Nilotinib NCT01201538

PTC 299 NCT00911248

Endostatin NCT02104323

(14 months) was significantly shorter than the median time to hearing decline (62 months) [93]. This study, along with prior reports, elucidated the natural history of individuals with NF2 to help to determine the most appropriate timing for

Different cellular pathways have been targeted in clinical trials for NF2 associated tumors (**Table 4**), with mixed responses. One of the most promising agents used in NF2 is bevacizumab, which was initially given on a compassionate use basis for adults with NF2-associated VS with severe disability [100, 101]. In these reports, 6 of 10 participants had ≥20% reduction in tumor volume and significantly improved hearing. The promising results led to designing two phase II clinical trials using bevacizumab in persons with NF2 who suffered from progressive hearing loss. A preliminary report from one of these 2 trials that enrolled 22 participants showed that the overall hearing and radiographic response rates were 41 and 23% respectively, though pediatric participants appeared to benefit less compared to adults (NCT01767792) [102]. Bevacizumab was used in a dose of 10 mg/kg every 2 weeks for 6 months, followed by 5 mg/kg every 3 weeks for

**(years)**

mTOR II ≥3 VS: 15% volume

mTOR II ≥15 VS: volume

mTOR II 16–65 VS: volume

mTOR Early phase I ≥18 VS and MEN:

EGFR/ErBb2 II 4–80 VS: 15% volume

EGFR/ErBb2 Early phase I ≥18 VS: tumor

PDGF, c-kit II ≥18 VS: 20% volume

VEGF II ≥18 VS: Tumor

**Endpoints Status**

No RR

No RR

Active, not recruiting

Active, not recruiting

23.5% RR

Completed, pending results

Active, not recruiting

Terminated

Terminated

pending results

reductions

reduction

reduction

tumor PK, molecular analysis

reduction

PK, molecular analysis

reduction

reduction

volume or WRS

II 16–30 Tumor volume Completed,

II ≥18 VS: 20% volume

Clinical trials for NF2 have been focused on vestibular schwannomas, since loss of hearing is often the most pressing concern in individuals with NF2. A group of 36 international researchers, physicians, representatives from the pharmaceutical industry, and patient advocates held a workshop to provide consensus recommendations to accelerate clinical trials progress in NF2 [99]. The group provided recommendations on participant selection, clinically meaningful and feasible endpoints, the clinical trials models most appropriate for NF2, and candidate therapeutic

**94**


*Abbreviations: c-kit, kit ligand or stem cell factor; EGFR/ErBb2, epidermal growth factor reception; HDAC, histone deacetylase; MEK, mitogen activated protein kinas; MEN, meningioma; mTOR, mammalian target of rapamycin; mTORC, mammalian target of rapamycin complex; PDGFR platelet-derived growth factor; PFS, progressionfree survival; PK, pharmacokinetics; VEGF, vascular endothelial growth factor; RR, radiographic response; VS. vestibular schwannoma; WRS, word recognition score.*

#### **Table 4.**

*Clinical trials in Neurofibromatosis type 2-associated vestibular schwannomas and meningiomas.*

NF2 shares many of the same targets identified in NF1; hence, some of the therapeutic agents tested in NF1 are being tested in NF2, including everolimus (NCT01345136), sorafenib, and selumetinib (NCT03095248). The dual mTROC1 and mTORC2 inhibitor, vistusertib (AZD2014), is used in a phase II study for NF2 patients with progressive or symptomatic meningiomas (NCT02831257). While the primary outcome for this study is the radiographic response rate for meningioma using volumetric MRI scans, the secondary outcomes include response assessment for VS and non-target meningioma using volumetric MRI. The NFCTC has approved using crizotinib, a MET and ALK inhibitor, in a phase II study for children and adults with NF2 associated progressive VS. There are promising preclinical studies identifying crizotinib as a potent inhibitor of NF2-null Schwann cell proliferation in vitro and tumor growth in vivo [103]. The goal for these clinical trials is to assess the hearing response rate as a clinically meaningful endpoint and to assess tolerability and long term effects of the tested agents, as well as identify biomarkers that can predict outcomes.

#### **5. Therapeutic development in Schwannomatosis**

Schwannomatosis (SWN), as the name implies, is characterized by the development of multiple peripheral nerve schwannomas, without concomitant involvement of the vestibular nerve, and, less commonly, meningiomas [108–110]. Since the schwannoma is the most common tumor in NF2 and SWN, there can be overlap between the two syndromes. SWN is a distinct entity with different clinical phenotype and genetic etiology from NF2. Germline mutations in SMARCB1 and LZTR1, both tumor suppressor genes, have been identified in SWN [111–113]. Unlike NF1 and NF2, pain is the most common symptom reported by individuals affected with SWN, with 68% reporting chronic pain in SWN in a retrospective study [114].

Surgical resection is considered the treatment of choice for symptomatic schwannomas for pain relief, though local recurrence is not uncommon. Patients usually require multiple surgical resections due to pain, focal neurologic deficits, or myelopathy [113]. Radiotherapy is reserved for those with life-threatening or enlarging tumors, and in rare occasions, malignant schwannomas. There are no available safety studies with respect to radiotherapy-induced malignant transformation in SWN, though theoretically it is possible given the available data from NF1, and NF2 studies.

Up to date, no clinical trials have been conducted in the setting of SWN and no known effective therapies exist. A case report was published using bevacizumab in one individual with SWN-associated refractory pain with a remarkable response in pain control [115].

#### **6. Clinical trials endpoints in neurofibromatoses**

Most early clinical trials for patients with neurofibromatoses used designs and endpoints similar to oncology trials. However, there are major differences in natural history, disease manifestations, and overall prognosis between patients with NF and those with cancers. Hence, there was an unmet need to establish standardized endpoints in NF clinical trials that will allow precise data interpretation and the ability to assess efficacy across different studies. The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration was established in 2011 at the Children's Tumor Foundation (CTF) meeting to achieve consensus about the design for future clinical trials with major emphasis on endpoints. The collaboration included 7 working groups; disease biomarkers; wholebody MRI; functional, visual, patient-reported, and neurocognitive outcome; and imaging for tumor response. Later, two more working groups were added; cutaneous neurofibromas, and patient representation [116].

The REiNS Collaboration published the initial recommendations for clinical trials endpoint in 2013 [117]. MRI with volumetric analysis was recommended as the standard imaging metric for pNF and VS in NF1 and NF2 clinical trials [118]. A 20% volume change was chosen to indicate an increase or decrease in the tumor size. MRI analysis requires central review to ensure consistent results. This is a time and resource intensive tool; thus, the development of methods that can be incorporated into routine clinical practice and can be performed more easily is warranted. Whole-body MRI imaging (WB-MRI) may serve as an endpoint in clinical trials that target multiple tumors. The working group concluded that while WB-MRI is feasible for identifying tumors using both 1.5 T and 3.0 T systems, choosing a standardized image acquisition and analysis methods is crucial for applying WB-MRIs as a tool for assessing tumors in NF [119]. For clinical trials targeting NF2-associated VS, the REiNS functional outcomes group endorsed the use of maximum word recognition score as the primary endpoint for hearing. The group recommended using the measurement of improvement in lip excursion (SMILE) system for studies of facial function [120]. For clinical trials targeting NF-associated OPG, the visual outcomes working group recommended the use

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appropriate observe-rated outcome measure.

approval for NF-associated tumors.

**7. Conclusion**

of visual acuity as the primary endpoint, as opposed to measurement of tumor size [121]. The group also recommended assessing the optic disc for pallor to allow accurate interpretation of the visual acuity. Regarding the neurocognitive outcomes, the working group concluded that The Digit Span (DS) subtest from the Wechsler scales is the most appropriate performance-based outcome measure, as it provides the best psychometrics, feasibility, and utility across a wide age range, and is extensively used in previous research [122]. For similar reasons, the Conners scale achieved the highest ratings of behavioral questionnaires and is considered the most

It is uncommon for pNF to cause airway compromise or pulmonary dysfunction, yet airway pNFs are clinically important. The REiNS functional outcomes group developed consensus recommendations for sleep and pulmonary outcome endpoints in airway pNFs [123]. The group endorsed using the apnea hypopnea index (AHI) as the primary sleep endpoint, and pulmonary resistance at 10 Hz (R10) of forced expiratory volume in 1 or 0.75 seconds (FEV1 or FEV 0.75) as the primary pulmonary endpoint. The group also identified secondary sleep and pulmonary outcomes. Measures of sleep and pulmonary function may be more clinically meaningful as endpoints than changes in tumor size in clinical trials targeting airway pNFs. Regarding patient-reported outcomes (PRO) of pain and physical function in NF clinical trials, the REiNS working group recommended the numeric rating scale-11 (NRS-11) to assess pain intensity for age 8 years and older [124]. To assess pain interference, the group recommended the Pain Interference Index in pediatric studies and the Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference Scale in adult studies. PROMIS Physical Function Scale was deemed the most appropriate for NF trials to assess the physical functioning domain. The REiNS disease biomarkers working group reported consensus recommendations to provide clinicians and researches with a common set of guidelines to collect and store biospecimens and for establishment of biobanks for neurofibromatoses [125]. The group described the existing biomarkers in NF and report consensus recommendations for standard operation procedures to standardize sample collection and methodology protocols to promote comparison between studies. Drug discovery is a very costly and lengthy process, which may take up to 10 years from first-in-human dosing to approval [126]. This process is usually preceded by years of extensive preclinical research to identify suitable targets for clinical development. The REiNS International Collaboration continues to work on developing consensus endpoints in NF clinical trials and to promote early engagement with FDA and other industry partners to accelerate the drug development and

The field of NF therapeutics is at inflection point. Several clinical trials have been conducted targeting various manifestations of NF and more studies are ongoing. The alignment of endpoints along with utilizing validated clinical outcomes measures represents a priority for therapeutic development for NF. Fortunately, there is a growing interest in NF, which is drawing the attention of pharmaceutical and biotechnology companies to grow the pipeline for NF targeted therapy. These efforts are combined with several ongoing laboratory and preclinical studies that provide unique opportunities to study the complex biology and natural history of NF-associated tumor. The US breakthrough therapy designation that was granted to Selumetinib in NF1 endorses the critical need for partnership among the major consortia and funders to accelerate the therapeutics development efforts in the NF field.

#### *Therapeutic Development in Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.89037*

*Neurofibromatosis - Current Trends and Future Directions*

**6. Clinical trials endpoints in neurofibromatoses**

ous neurofibromas, and patient representation [116].

and NF2 studies.

pain control [115].

of the vestibular nerve, and, less commonly, meningiomas [108–110]. Since the schwannoma is the most common tumor in NF2 and SWN, there can be overlap between the two syndromes. SWN is a distinct entity with different clinical phenotype and genetic etiology from NF2. Germline mutations in SMARCB1 and LZTR1, both tumor suppressor genes, have been identified in SWN [111–113]. Unlike NF1 and NF2, pain is the most common symptom reported by individuals affected with SWN, with 68% reporting chronic pain in SWN in a retrospective study [114]. Surgical resection is considered the treatment of choice for symptomatic schwannomas for pain relief, though local recurrence is not uncommon. Patients usually require multiple surgical resections due to pain, focal neurologic deficits, or myelopathy [113]. Radiotherapy is reserved for those with life-threatening or enlarging tumors, and in rare occasions, malignant schwannomas. There are no available safety studies with respect to radiotherapy-induced malignant transformation in SWN, though theoretically it is possible given the available data from NF1,

Up to date, no clinical trials have been conducted in the setting of SWN and no known effective therapies exist. A case report was published using bevacizumab in one individual with SWN-associated refractory pain with a remarkable response in

Most early clinical trials for patients with neurofibromatoses used designs and endpoints similar to oncology trials. However, there are major differences in natural history, disease manifestations, and overall prognosis between patients with NF and those with cancers. Hence, there was an unmet need to establish standardized endpoints in NF clinical trials that will allow precise data interpretation and the ability to assess efficacy across different studies. The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration was established in 2011 at the Children's Tumor Foundation (CTF) meeting to achieve consensus about the design for future clinical trials with major emphasis on endpoints. The collaboration included 7 working groups; disease biomarkers; wholebody MRI; functional, visual, patient-reported, and neurocognitive outcome; and imaging for tumor response. Later, two more working groups were added; cutane-

The REiNS Collaboration published the initial recommendations for clinical trials endpoint in 2013 [117]. MRI with volumetric analysis was recommended as the standard imaging metric for pNF and VS in NF1 and NF2 clinical trials [118]. A 20% volume change was chosen to indicate an increase or decrease in the tumor size. MRI analysis requires central review to ensure consistent results. This is a time and resource intensive tool; thus, the development of methods that can be incorporated into routine clinical practice and can be performed more easily is warranted. Whole-body MRI imaging (WB-MRI) may serve as an endpoint in clinical trials that target multiple tumors. The working group concluded that while WB-MRI is feasible for identifying tumors using both 1.5 T and 3.0 T systems, choosing a standardized image acquisition and analysis methods is crucial for applying WB-MRIs as a tool for assessing tumors in NF [119]. For clinical trials targeting NF2-associated VS, the REiNS functional outcomes group endorsed the use of maximum word recognition score as the primary endpoint for hearing. The group recommended using the measurement of improvement in lip excursion (SMILE) system for studies of facial function [120]. For clinical trials targeting NF-associated OPG, the visual outcomes working group recommended the use

**96**

of visual acuity as the primary endpoint, as opposed to measurement of tumor size [121]. The group also recommended assessing the optic disc for pallor to allow accurate interpretation of the visual acuity. Regarding the neurocognitive outcomes, the working group concluded that The Digit Span (DS) subtest from the Wechsler scales is the most appropriate performance-based outcome measure, as it provides the best psychometrics, feasibility, and utility across a wide age range, and is extensively used in previous research [122]. For similar reasons, the Conners scale achieved the highest ratings of behavioral questionnaires and is considered the most appropriate observe-rated outcome measure.

It is uncommon for pNF to cause airway compromise or pulmonary dysfunction, yet airway pNFs are clinically important. The REiNS functional outcomes group developed consensus recommendations for sleep and pulmonary outcome endpoints in airway pNFs [123]. The group endorsed using the apnea hypopnea index (AHI) as the primary sleep endpoint, and pulmonary resistance at 10 Hz (R10) of forced expiratory volume in 1 or 0.75 seconds (FEV1 or FEV 0.75) as the primary pulmonary endpoint. The group also identified secondary sleep and pulmonary outcomes. Measures of sleep and pulmonary function may be more clinically meaningful as endpoints than changes in tumor size in clinical trials targeting airway pNFs. Regarding patient-reported outcomes (PRO) of pain and physical function in NF clinical trials, the REiNS working group recommended the numeric rating scale-11 (NRS-11) to assess pain intensity for age 8 years and older [124]. To assess pain interference, the group recommended the Pain Interference Index in pediatric studies and the Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference Scale in adult studies. PROMIS Physical Function Scale was deemed the most appropriate for NF trials to assess the physical functioning domain. The REiNS disease biomarkers working group reported consensus recommendations to provide clinicians and researches with a common set of guidelines to collect and store biospecimens and for establishment of biobanks for neurofibromatoses [125]. The group described the existing biomarkers in NF and report consensus recommendations for standard operation procedures to standardize sample collection and methodology protocols to promote comparison between studies.

Drug discovery is a very costly and lengthy process, which may take up to 10 years from first-in-human dosing to approval [126]. This process is usually preceded by years of extensive preclinical research to identify suitable targets for clinical development. The REiNS International Collaboration continues to work on developing consensus endpoints in NF clinical trials and to promote early engagement with FDA and other industry partners to accelerate the drug development and approval for NF-associated tumors.

#### **7. Conclusion**

The field of NF therapeutics is at inflection point. Several clinical trials have been conducted targeting various manifestations of NF and more studies are ongoing. The alignment of endpoints along with utilizing validated clinical outcomes measures represents a priority for therapeutic development for NF. Fortunately, there is a growing interest in NF, which is drawing the attention of pharmaceutical and biotechnology companies to grow the pipeline for NF targeted therapy. These efforts are combined with several ongoing laboratory and preclinical studies that provide unique opportunities to study the complex biology and natural history of NF-associated tumor. The US breakthrough therapy designation that was granted to Selumetinib in NF1 endorses the critical need for partnership among the major consortia and funders to accelerate the therapeutics development efforts in the NF field.

### **Disclosures**

Mina Lobbous and Bruce Korf report no disclosures relative to the manuscript.

#### **Author details**

Mina Lobbous1 \* and Bruce R. Korf<sup>2</sup>

1 Department of Neurology, Division of NeuroOncology, University of Alabama at Birmingham, USA

2 Wayne H. and Sara Crews Finley Endowed Chair in Medical Genetics, University of Alabama at Birmingham, USA

\*Address all correspondence to: mlobbous@uabmc.edu

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**99**

*Therapeutic Development in Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.89037*

Compston DAS. Von recklinghausen neurofibromatosisa clinical and population study in south-east Wales. Brain. 1988;**111**(6):1355-1381. DOI:

[8] Dombi E, Solomon J, Gillespie AJ, Fox E, Balis FM, et al. NF1 plexiform

volumetric MRI. Neurology. February 2007;**68**(9):643-647. DOI: 10.1212/01.

[9] Prada CE et al. Pediatric plexiform neurofibromas: Impact on morbidity and mortality in neurofibromatosis type 1. The Journal of Pediatrics. 2012;**160**(3):461-467. DOI: 10.1016/j.

[10] Widemann BC et al. Phase 2 randomized, flexible crossover, doubleblinded, placebo-controlled trial of the farnesyltransferase inhibitor tipifarnib in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. Neuro-Oncology. 2014;**16**(5):707-718.

DOI: 10.1093/neuonc/nou004

[11] Weiss B et al. Sirolimus for progressive neurofibromatosis type 1–associated plexiform neurofibromas: A neurofibromatosis clinical trials consortium phase II study. Neuro-Oncology. 2015;**17**(4):596-603. DOI:

[12] Robertson KA, Nalepa G, Yang FC, Bowers DC, Ho CY, Hutchins GD, et al. Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: A phase 2 trial. The Lancet Oncology.

2012;**13**(12):1218-1224. ISSN: 1470-2045. DOI: 10.1016/S1470-2045(12)70414-X

[13] Ratner N, Miller SJ. A RASopathy gene commonly mutated in cancer: The neurofibromatosis type 1 tumour suppressor. Nature Reviews. Cancer. 2015;**15**(5):290-301. DOI: 10.1038/

[14] Gupta A et al. Phase I study of thalidomide for the treatment of plexiform neurofibroma in

10.1093/neuonc/nou235

nrc3911

neurofibroma growth rate by

wnl.0000250332.89420.e6

jpeds.2011.08.051

[2] Birth incidence and prevalence of tumor-prone syndromes: Estimates from a UK family genetic register service—Evans. American Journal of Medical Genetics Part A—Wiley Online Library. 2010. Available from: https:// onlinelibrary.wiley.com/doi/full/10.1002/ ajmg.a.33139 [Accessed: 16 June 2019]

[3] Packer RJ et al. Neurofibromatosis clinical trial consortium. Journal of Child Neurology. 2018;**33**(1):82-91. DOI: 10.1177/0883073817739196

[4] Meeting Library. SPRINT: Phase II Study of the MEK 1/2 Inhibitor Selumetinib (AZD6244, ARRY-142886) in Children with Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN). Available from: https://meetinglibrary.asco.org/record/ 159508/abstract [Accessed: 24 June 2019]

[5] La Rosa S et al. Delivering on the vision of bench to bedside: A rare disease funding community collaboration to develop effective therapies for neurofibromatosis type 1 tumors. BioRxiv. 2019:552976. DOI:

[6] Tucker T, Friedman JM,

wnl.0000250332.89420.e6

Friedrich RE, et al. Longitudinal study of neurofibromatosis 1 associated plexiform neurofibromas. Journal of Medical Genetics. 2009;**46**(2):81-85. DOI: 10.1136/jmg.2008.061051

[7] Dombi E, Solomon J, Gillespie AJ, Fox E, Balis FM, Patronas N, et al. NF1 plexiform neurofibroma growth rate by volumetric MRI. Neurology. 2007;**68**(9):643-647. DOI: 10.1212/01.

10.1101/552976

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*Therapeutic Development in Neurofibromatosis DOI: http://dx.doi.org/10.5772/intechopen.89037*

#### **References**

*Neurofibromatosis - Current Trends and Future Directions*

Mina Lobbous and Bruce Korf report no disclosures relative to the manuscript.

**Disclosures**

**98**

**Author details**

Mina Lobbous1

Birmingham, USA

of Alabama at Birmingham, USA

provided the original work is properly cited.

\* and Bruce R. Korf<sup>2</sup>

\*Address all correspondence to: mlobbous@uabmc.edu

1 Department of Neurology, Division of NeuroOncology, University of Alabama at

2 Wayne H. and Sara Crews Finley Endowed Chair in Medical Genetics, University

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

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article/19/2/289/3038131 [Accessed: 19

[22] Zehou O et al. Absence of efficacy of everolimus in neurofibromatosis 1-related plexiform neurofibromas: Results from a phase 2a trial. Journal of Investigative Dermatology. 2019;**139**(3):718-720. DOI:

[23] Robertson KA, Nalepa G, Yang FC, Bowers DC, Ho CY et al. Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: A phase 2 trial. The Lancet Oncology. 2012;**13**(12):1218-1224. ISSN: 1470-2045. DOI: 10.1016/S1470-2045(12)70414-X

[24] Hittson L et al. Phase I study of pexidartinib (PLX3397) in children with refractory leukemias and solid tumors including neurofibromatosis type I (NF1) related plexiform neurofibromas (PN). Journal of Clinical Oncology. 2017;**35**(15\_suppl):10546-10546. DOI: 10.1200/JCO.2017.35.15\_suppl.10546

[25] Weiss B et al. NFM-06. NF106: Phase 2 trial of the mek inhibitor PD-0325901 in adolescents and adults with nf1-related plexiform neurofibromas: An NF clinical trials consortium study. Neuro-Oncology. 2018;**20**(suppl\_2):i143-i143. DOI: 10.1093/neuonc/noy059.514

[26] Dombi E et al. Activity of

NEJMoa1605943

selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. The New England Journal of Medicine. 2016;**375**(26):2550-2560. DOI: 10.1056/

[27] Lewis RA et al. Von Recklinghausen

neurofibromatosis. II. Incidence

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wnl.0000042321.94839.78

[15] Weiss B, Widemann BC, Wolters P, Dombi E, Vinks A,

plexiform neurofibromas: A neurofibromatosis. Clinical Trials Consortium Phase II study. Neuro-Oncology. April 2015;**17**(4):596-603.

DOI: 10.1093/neuonc/nou235

DOI: 10.1002/pbc.24281

pediatrneurol.2007.01.009

10.1002/pbc.25041

[18] Widemann BC et al. Phase II trial of pirfenidone in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. Pediatric Blood & Cancer. 2014;**61**(9):1598-1602. DOI:

[19] Widemann BC, Dombi E, Gillespie A, Wolters PL, Belasco J, Goldman S, et al. Phase 2 randomized, flexible crossover, double-blinded, placebo-controlled trial of the

farnesyltransferase inhibitor tipifarnib in children and young adults with neurofibromatosis type 1 and

progressive plexiform neurofibromas. Neuro-Oncology. May 2014;**16**(5):707- 718. DOI: 10.1093/neuonc/nou004

[20] Phase II trial of pegylated interferon Alfa-2b in young patients with neurofibromatosis type 1 and unresectable plexiform neurofibromas. Neuro-Oncology. Oxford Academic.

[16] Kim AR et al. Phase I trial and pharmacokinetic study of sorafenib in children with neurofibromatosis type I and plexiform neurofibromas. Pediatric Blood & Cancer. 2013;**60**(3):396-401.

[17] Babovic-Vuksanovic D et al. Phase I trial of pirfenidone in children with neurofibromatosis 1 and plexiform neurofibromas. Pediatric Neurology. 2007;**36**(5):293-300. DOI: 10.1016/j.

Cantor A, et al. Sirolimus for progressive neurofibromatosis type 1–associated

**100**

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### *Edited by Francesco Signorelli and Raffaella Messina*

Neurofibromatosis, one of the most common genetic disorders, is a group of three conditions—Neurofibromatosis 1, Neurofibromatosis 2 and Schwannomatosis that share some clinical features, such as the presence of cranial and spinal nerve sheet tumors. However, they differ in type of genetic disorder, age of clinical onset, manifestations, management and prognosis. Due to multisystem involvement, a multidisciplinary treatment approach that includes research is ideal. This book provides a systematic, comprehensive and updated outline of Neurofibromatosis. It is a useful reference for clinicians, researchers and students.

Published in London, UK © 2020 IntechOpen © Sinhyu / iStock

Neurofibromatosis - Current Trends and Future Directions

Neurofibromatosis

Current Trends and Future Directions

*Edited by Francesco Signorelli* 

*and Raffaella Messina*