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MEK Inhibitors for Neurofibromatosis Type 1 Manifestations: Clinical Evidence and Consensus

de Blank, Peter M K; Gross, Andrea M; Akshintala, Srivandana; Blakeley, Jaishri O; Bollag, Gideon; Cannon, Ashley; Dombi, Eva; Fangusaro, Jason; Gelb, Bruce D; Hargrave, Darren; Kim, AeRang; Klesse, Laura J; Loh, Mignon; Martin, Staci; Moertel, Christopher; Packer, Roger; Payne, Jonathan M; Rauen, Katherine A; Rios, Jonathan J; Robison, Nathan; Schorry, Elizabeth K; Shannon, Kevin; Stevenson, David A; Stieglitz, Elliot; Ullrich, Nicole J; Walsh, Karin S; Weiss, Brian D; Wolters, Pamela L; Yohay, Kaleb; Yohe, Marielle E; Widemann, Brigitte C; Fisher, Michael J
The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated protein kinase kinase inhibitors (MEKi) block downstream targets of RAS. The recent regulatory approvals of the MEKi selumetinib for inoperable symptomatic plexiform neurofibromas in children with NF1 has made it the first medical therapy approved for this indication in the United States, the European Union and elsewhere. Several recently published and ongoing clinical trials have demonstrated that MEKi may have potential benefit for a variety of other NF1 manifestations, and there is broad interest in the field regarding the appropriate clinical use of these agents. In this review, we present the current evidence regarding the use of existing MEKi for a variety of NF1-related manifestations, including tumor (neurofibromas, malignant peripheral nerve sheath tumors, low grade glioma, and juvenile myelomonocytic leukemia) and non-tumor (bone, pain, and neurocognitive) manifestations. We discuss the potential utility of MEKi in related genetic conditions characterized by overactivation of the RAS pathway (RASopathies). In addition, we review practical treatment considerations for the use of MEKi as well as provide consensus recommendations regarding their clinical use from a panel of experts.
PMID: 35788692
ISSN: 1523-5866
CID: 5280232

Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation

Plotkin, Scott R; Messiaen, Ludwine; Legius, Eric; Pancza, Patrice; Avery, Robert A; Blakeley, Jaishri O; Babovic-Vuksanovic, Dusica; Ferner, Rosalie; Fisher, Michael J; Friedman, Jan M; Giovannini, Marco; Gutmann, David H; Hanemann, Clemens Oliver; Kalamarides, Michel; Kehrer-Sawatzki, Hildegard; Korf, Bruce R; Mautner, Victor-Felix; MacCollin, Mia; Papi, Laura; Rauen, Katherine A; Riccardi, Vincent; Schorry, Elizabeth; Smith, Miriam J; Stemmer-Rachamimov, Anat; Stevenson, David A; Ullrich, Nicole J; Viskochil, David; Wimmer, Katharina; Yohay, Kaleb; Huson, Susan M; Wolkenstein, Pierre; Evans, Dafydd Gareth
PURPOSE/OBJECTIVE:Neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are genetically distinct tumor predisposition syndromes with overlapping phenotypes. We sought to update the diagnostic criteria for NF2 and SWN by incorporating recent advances in genetics, ophthalmology, neuropathology, and neuroimaging. METHODS:We used a multistep process, beginning with a Delphi method involving global disease experts and subsequently involving non-neurofibromatosis clinical experts, patients, and foundations/patient advocacy groups. RESULTS:We reached consensus on the minimal clinical and genetic criteria for diagnosing NF2 and SWN. These criteria incorporate mosaic forms of these conditions. In addition, we recommend updated nomenclature for these disorders to emphasize their phenotypic overlap and to minimize misdiagnosis with neurofibromatosis type 1. CONCLUSION/CONCLUSIONS:The updated criteria for NF2 and SWN incorporate clinical features and genetic testing, with a focus on using molecular data to differentiate the 2 conditions. It is likely that continued refinement of these new criteria will be necessary as investigators study the diagnostic properties of the revised criteria and identify new genes associated with SWN. In the revised nomenclature, the term "neurofibromatosis 2" has been retired to improve diagnostic specificity.
PMID: 35674741
ISSN: 1530-0366
CID: 5248402

Management of Neurofibromatosis Type 1-Associated Plexiform Neurofibromas

Fisher, Michael J; Blakeley, Jaishri O; Weiss, Brian D; Dombi, Eva; Ahlawat, Shivani; Akshintala, Srivandana; Belzberg, Allan J; Bornhorst, Miriam; Bredella, Miriam A; Cai, Wenli; Ferner, Rosalie E; Gross, Andrea M; Harris, Gordon J; Listernick, Robert; Ly, Ina; Martin, Staci; Mautner, Victor-F; Salamon, Johannes M; Salerno, Kilian E; Spinner, Robert J; Staedtke, Verena; Ullrich, Nicole J; Upadhyaya, Meena; Wolters, Pamela L; Yohay, Kaleb; Widemann, Brigitte C
Plexiform Neurofibromas (PN) are a common manifestation of the genetic disorder neurofibromatosis type 1 (NF1). These benign nerve sheath tumors often cause significant morbidity, with treatment options limited historically to surgery. There have been tremendous advances over the past two decades in our understanding of PN, and the recent regulatory approvals of the MEK inhibitor selumetinib are reshaping the landscape for PN management. At present, there is no agreed upon PN definition, diagnostic evaluation, surveillance strategy, or clear indications for when to initiate treatment and selection of treatment modality. In this review, we address these questions via consensus recommendations from a panel of multi-disciplinary NF1 experts.
PMID: 35657359
ISSN: 1523-5866
CID: 5283582

Awareness and agreement with neurofibromatosis care guidelines among U.S. neurofibromatosis specialists

Merker, Vanessa L; Knight, Pamela; Radtke, Heather B; Yohay, Kaleb; Ullrich, Nicole J; Plotkin, Scott R; Jordan, Justin T
INTRODUCTION/BACKGROUND:The neurofibromatoses (NF) are a group of rare, genetic diseases sharing a predisposition to develop multiple benign nervous system tumors. Given the wide range of NF symptoms and medical specialties involved in NF care, we sought to evaluate the level of awareness of, and agreement with, published NF clinical guidelines among NF specialists in the United States. METHODS:An anonymous, cross-sectional, online survey was distributed to U.S.-based NF clinicians. Respondents self-reported demographics, practice characteristics, awareness of seven NF guideline publications, and level of agreement with up to 40 individual recommendations using a 5-point Likert scale. We calculated the proportion of recommendations that each clinician rated "strongly agree", and assessed for differences in guideline awareness and agreement by respondent characteristics. RESULTS:Sixty-three clinicians (49% female; 80% academic practice) across > 8 medical specialties completed the survey. Awareness of each guideline publication ranged from 53%-79% of respondents; specialists had higher awareness of publications endorsed by their medical professional organization (p < 0.05). The proportion of respondents who "strongly agree" with individual recommendations ranged from 17%-83%; for 16 guidelines, less than 50% of respondents "strongly agree". There were no significant differences in overall agreement with recommendations based on clinicians' gender, race, specialty, years in practice, practice type (academic/private practice/other), practice location (urban/suburban/rural), or involvement in NF research (p > 0.05 for all). CONCLUSIONS:We identified wide variability in both awareness of, and agreement with, published NF care guidelines among NF experts. Future quality improvement efforts should focus on evidence-based, consensus-driven methods to update and disseminate guidelines across this multi-specialty group of providers. Patients and caregivers should also be consulted to proactively anticipate barriers to accessing and implementing guideline-driven care. These recommendations for improving guideline knowledge and adoption may also be useful for other rare diseases requiring multi-specialty care coordination.
PMCID:8832755
PMID: 35144646
ISSN: 1750-1172
CID: 5156882

REiNS: Reliability of Handheld Dynamometry to Measure Focal Muscle Weakness in Neurofibromatosis Types 1 and 2

Akshintala, Srivandana; Khalil, Nashwa; Yohay, Kaleb; Muzikansky, Alona; Allen, Jeffrey; Yaffe, Anna; Gross, Andrea M; Fisher, Michael J; Blakeley, Jaishri O; Oberlander, Beverly; Pudel, Miriam; Engelson, Celia; Obletz, Jaime; Mitchell, Carole; Widemann, Brigitte C; Stevenson, David A; Plotkin, Scott R
OBJECTIVE:To determine a suitable outcome measure for assessing muscle strength in neurofibromatosis type 1 (NF1) and type 2 (NF2) clinical trials, we evaluated the intra-observer reliability of hand-held dynamometry (HHD) and developed consensus recommendations for its use in neurofibromatosis clinical trials. METHODS:Patients ≥5 years with weakness in at least 1 muscle group by manual muscle testing (MMT) were eligible. Maximal isometric muscle strength of a weak muscle group and the biceps of the dominant arm were measured by HHD. An average of 3 repetitions per session was used as an observation, and 3 sessions with rest period between each were performed on the same day by a single observer. Intra- and inter-session intraclass correlation (ICC) and coefficient of variation (CV) were calculated to assess reliability and measurement error. RESULTS:Twenty NF1 and 13 NF2 patients enrolled; median age was 12 years (interquartile range (IQR) 9-17) and 29 years (IQR 22-38) respectively. By MMT, weak muscle strength ranged from 2-/5 to 4+/5. Biceps strength was 5/5 in all patients. Inter-session ICC for the weak muscles were 0.98 and 0.99 in the NF1 and NF2 cohorts respectively and for biceps were 0.97 and 0.97 respectively. The median CV for average session strength were 5.4% (IQR 2.6%-7.3%) and 2.9% (IQR 2.0%-6.2%) for weak muscles and biceps respectively. CONCLUSION/CONCLUSIONS:HHD performed by a trained examiner with a well-defined protocol is a reliable technique to measure muscle strength in NF1 and NF2. Recommendations for strength testing in NF1 and NF2 trials are provided.
PMID: 34230196
ISSN: 1526-632x
CID: 4932172

Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

Legius, Eric; Messiaen, Ludwine; Wolkenstein, Pierre; Pancza, Patrice; Avery, Robert A; Berman, Yemima; Blakeley, Jaishri; Babovic-Vuksanovic, Dusica; Cunha, Karin Soares; Ferner, Rosalie; Fisher, Michael J; Friedman, Jan M; Gutmann, David H; Kehrer-Sawatzki, Hildegard; Korf, Bruce R; Mautner, Victor-Felix; Peltonen, Sirkku; Rauen, Katherine A; Riccardi, Vincent; Schorry, Elizabeth; Stemmer-Rachamimov, Anat; Stevenson, David A; Tadini, Gianluca; Ullrich, Nicole J; Viskochil, David; Wimmer, Katharina; Yohay, Kaleb; Huson, Susan M; Evans, D Gareth; Plotkin, Scott R
PURPOSE/OBJECTIVE:By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). METHODS:We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. RESULTS:We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. CONCLUSION/CONCLUSIONS:The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.
PMID: 34012067
ISSN: 1530-0366
CID: 4894862

Slowing late infantile Batten disease by direct brain parenchymal administration of a rh.10 adeno-associated virus expressing CLN2

Sondhi, Dolan; Kaminsky, Stephen M; Hackett, Neil R; Pagovich, Odelya E; Rosenberg, Jonathan B; De, Bishnu P; Chen, Alvin; Van de Graaf, Benjamin; Mezey, Jason G; Mammen, Grace W; Mancenido, Denesy; Xu, Fang; Kosofsky, Barry; Yohay, Kaleb; Worgall, Stefan; Kaner, Robert J; Souwedaine, Mark; Greenwald, Bruce M; Kaplitt, Michael; Dyke, Jonathan P; Ballon, Douglas J; Heier, Linda A; Kiss, Szilard; Crystal, Ronald G
Late infantile Batten disease (CLN2 disease) is an autosomal recessive, neurodegenerative lysosomal storage disease caused by mutations in the CLN2 gene encoding tripeptidyl peptidase 1 (TPP1). We tested intraparenchymal delivery of AAVrh.10hCLN2, a nonhuman serotype rh.10 adeno-associated virus vector encoding human CLN2, in a nonrandomized trial consisting of two arms assessed over 18 months: AAVrh.10hCLN2-treated cohort of 8 children with mild to moderate disease and an untreated, Weill Cornell natural history cohort consisting of 12 children. The treated cohort was also compared to an untreated European natural history cohort of CLN2 disease. The vector was administered through six burr holes directly to 12 sites in the brain without immunosuppression. In an additional safety assessment under a separate protocol, five children with severe CLN2 disease were treated with AAVrh.10hCLN2. The therapy was associated with a variety of expected adverse events, none causing long-term disability. Induction of systemic anti-AAVrh.10 immunity was mild. After therapy, the treated cohort had a 1.3- to 2.6-fold increase in cerebral spinal fluid TPP1. There was a slower loss of gray matter volume in four of seven children by MRI and a 42.4 and 47.5% reduction in the rate of decline of motor and language function, compared to Weill Cornell natural history cohort (P < 0.04) and European natural history cohort (P < 0.0001), respectively. Intraparenchymal brain administration of AAVrh.10hCLN2 slowed the progression of disease in children with CLN2 disease. However, improvements in vector design and delivery strategies will be necessary to halt disease progression using gene therapy.
PMID: 33268510
ISSN: 1946-6242
CID: 4694282

The Use of MEK Inhibitors in Neurofibromatosis Type 1-Associated Tumors and Management of Toxicities

Klesse, Laura J; Jordan, Justin T; Radtke, Heather B; Rosser, Tena; Schorry, Elizabeth; Ullrich, Nicole; Viskochil, David; Knight, Pamela; Plotkin, Scott R; Yohay, Kaleb
Early-phase clinical trials using oral inhibitors of MEK, the mitogen-activated protein kinase kinase, have demonstrated benefit for patients with neurofibromatosis type 1 (NF1)-associated tumors, particularly progressive low-grade gliomas and plexiform neurofibromas. Given this potential of MEK inhibition as an effective medical therapy, the use of targeted agents in the NF1 population is likely to increase substantially. For clinicians with limited experience prescribing MEK inhibitors, concern about managing these treatments may be a barrier to use. In this manuscript, the Clinical Care Advisory Board of the Children's Tumor Foundation reviews the published experience with MEK inhibitors in NF1 and outlines recommendations for side-effect management, as well as monitoring guidelines. These recommendations can serve as a beginning framework for NF providers seeking to provide the most effective treatments for their patients. IMPLICATIONS FOR PRACTICE: Neurofibromatosis type 1 (NF1) clinical care is on the cusp of a transformative shift. With the success of recent clinical trials using MEK inhibitors, an increasing number of NF1 patients are being treated with MEK inhibitors for both plexiform neurofibromas and low-grade gliomas. The use of MEK inhibitors is likely to increase substantially with the expected upcoming approval of selumetinib for a specific indication for treatment of plexiform neurofibromas in NF1. Given these changes, the Clinical Care Advisory Board of the Children's Tumor Foundation has identified a need within the NF1 clinical community for guidance for the safe and effective use of MEK inhibitors for NF1-related tumors. This article provides a review of the published experience of MEK inhibitors in NF1 and provides recommendations for monitoring and management of side effects.
PMID: 32272491
ISSN: 1549-490x
CID: 4379022

Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276 and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1

Koczkowska, Magdalena; Callens, Tom; Chen, Yunjia; Gomes, Alicia; Hicks, Alesha D; Sharp, Angela; Johns, Eric; Uhas, Kim Armfield; Armstrong, Linlea; Bosanko, Katherine Armstrong; Babovic-Vuksanovic, Dusica; Baker, Laura; Basel, Donald G; Bengala, Mario; Bennett, James T; Chambers, Chelsea; Clarkson, Lola K; Clementi, Maurizio; Cortés, Fanny M; Cunningham, Mitch; D'Agostino, M Daniela; Delatycki, Martin B; Digilio, Maria C; Dosa, Laura; Esposito, Silvia; Fox, Stephanie; Freckmann, Mary-Louise; Fauth, Christine; Giugliano, Teresa; Giustini, Sandra; Goetsch, Allison; Goldberg, Yael; Greenwood, Robert S; Griffis, Cristin; Gripp, Karen W; Gupta, Punita; Haan, Eric; Hachen, Rachel K; Haygarth, Tamara L; Hernández-Chico, Concepción; Hodge, Katelyn; Hopkin, Robert J; Hudgins, Louanne; Janssens, Sandra; Keller, Kory; Kelly-Mancuso, Geraldine; Kochhar, Aaina; Korf, Bruce R; Lewis, Andrea M; Liebelt, Jan; Lichty, Angie; Listernick, Robert H; Lyons, Michael J; Maystadt, Isabelle; Ojeda, Mayra Martinez; McDougall, Carey; McGregor, Lesley K; Melis, Daniela; Mendelsohn, Nancy; Nowaczyk, Malgorzata J M; Ortenberg, June; Panzer, Karin; Pappas, John G; Pierpont, Mary Ella; Piluso, Giulio; Pinna, Valentina; Pivnick, Eniko K; Pond, Dinel A; Powell, Cynthia M; Rogers, Caleb; Shahar, Noa Ruhrman; Rutledge, S Lane; Saletti, Veronica; Sandaradura, Sarah A; Santoro, Claudia; Schatz, Ulrich A; Schreiber, Allison; Scott, Daryl A; Sellars, Elizabeth A; Sheffer, Ruth; Siqveland, Elizabeth; Slopis, John M; Smith, Rosemarie; Spalice, Alberto; Stockton, David W; Streff, Haley; Theos, Amy; Tomlinson, Gail E; Tran, Grace; Trapane, Pamela L; Trevisson, Eva; Ullrich, Nicole J; Van den Ende, Jenneke; Schrier Vergano, Samantha A; Wallace, Stephanie E; Wangler, Michael F; Weaver, David D; Yohay, Kaleb H; Zackai, Elaine; Zonana, Jonathan; Zurcher, Vickie; Claes, Kathleen B M; Eoli, Marica; Martin, Yolanda; Wimmer, Katharina; De Luca, Alessandro; Legius, Eric; Messiaen, Ludwine M
We report 281 individuals carrying a pathogenic recurrent NF1 missense variants at p.Met1149, p.Arg1276 or p.Lys1423, representing three non-truncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% CI, 20.5%-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276 or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared to the "classic" NF1-affected cohorts (all P<0.0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all P<0.0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (P<0.0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population. This article is protected by copyright. All rights reserved.
PMID: 31595648
ISSN: 1098-1004
CID: 4129722

The MEK inhibitor selumetinib reduces spinal neurofibroma burden in patients with NF1 and plexiform neurofibromas

Jackson, Sadhana; Baker, Eva H; Gross, Andrea M; Whitcomb, Patricia; Baldwin, Andrea; Derdak, Joanne; Tibery, Cecilia; Desanto, Jennifer; Carbonell, Amanda; Yohay, Kaleb; O'Sullivan, Geraldine; Chen, Alice P; Widemann, Brigitte C; Dombi, Eva
Background/UNASSIGNED:Spinal neurofibromas (SNFs) in neurofibromatosis type 1 (NF1) can cause progressive spinal cord compression and neurological dysfunction. The MEK inhibitor selumetinib shrinks the majority of plexiform neurofibromas (PNs) in patients with NF1. We assessed the effect of selumetinib on SNF. Methods/UNASSIGNED:/dose twice daily (max 50 mg b.i.d.; 1 cycle = 28 days). We qualitatively assessed the effect of selumetinib on SNF-related spinal canal distortion, cerebrospinal fluid distribution, and spinal cord deformity on MRI. Results/UNASSIGNED:Twenty-four patients (18 male), median age 16.9 years (range, 6.2-60.3), had SNF, 22 of which were associated with the same nerves as the target PN assessed on the clinical trial. Twenty patients had spinal cord deformity. Twenty-three patients completed at least 12 treatment cycles to date. Eighteen patients showed subtle to a marked improvement in SNF burden, 5 remained stable, and no worsening was observed during treatment. Conclusions/UNASSIGNED:This is the first study describing the effect of selumetinib on SNF. Of 24 patients, 18 exhibited some improvement of SNF burden on imaging. These findings suggest that selumetinib may prevent the worsening of cord compression, potentially reducing the need for surgical interventions in select patients or benefitting patients who do not have a surgical option. Prospective evaluation of the clinical benefit of selumetinib for SNF is warranted.
PMCID:7486535
PMID: 32939452
ISSN: 2632-2498
CID: 4606452