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Outcome of Patients With Malignant Peripheral Nerve Sheath Tumors Enrolled on Sarcoma Alliance for Research Through Collaboration (SARC) Phase II Trials

Akshintala, Srivandana; Mallory, Nicole C; Lu, Yao; Ballman, Karla V; Schuetze, Scott M; Chugh, Rashmi; Maki, Robert G; Reinke, Denise K; Widemann, Brigitte C; Kim, Ae Rang
BACKGROUND:Evaluation of prior phase II trials for malignant peripheral nerve sheath tumors (MPNST) may help develop more suitable trial endpoints in future studies. METHODS:We analyzed outcomes of patients with recurrent or unresectable/metastatic MPNST enrolled on prior Sarcoma Alliance for Research through Collaboration (SARC) phase II trials and estimated the progression-free survival (PFS). PFS from SARC006 (NCT00304083), the phase II trial of upfront chemotherapy in chemotherapy naïve patients, was analyzed separately. Impact of baseline enrollment characteristics on PFS was evaluated. RESULTS:Sixty-four patients (29 male, 35 female, median age 39 years (range 15-81)) with MPNST were enrolled on 1 of 5 trials of single agent or combination therapy that were determined to be inactive. Patients had received a median of 1 (range 0-5) prior systemic therapy, and most had undergone prior surgery (77%) and radiation (61%). Seventy-three percent had metastatic disease at enrollment. Median PFS was 1.77 months (95% CI, 1.61-3.45), and the PFS rate at 4 months was 15%. Greater number of prior systemic therapies and worse performance status were associated with inferior PFS. There was no significant difference in PFS based on age at enrollment, treatment trial, response criteria, presence of metastatic disease, disease site at enrollment, and prior surgery or radiation. In comparison, on the SARC006 trial the PFS rate at 4 months was 94% in 40 patients. CONCLUSION/CONCLUSIONS:These data provide a historical baseline PFS that may be used as a comparator in future clinical trials for patients with MPNST.
PMID: 36724001
ISSN: 1549-490x
CID: 5420102

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

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

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

Longitudinal evaluation of peripheral nerve sheath tumors in neurofibromatosis type 1: Growth analysis of plexiform neurofibromas and distinct nodular lesions

Akshintala, Srivandana; Baldwin, Andrea; Liewehr, David J; Goodwin, Anne; Blakeley, Jaishri O; Gross, Andrea M; Steinberg, Seth M; Dombi, Eva; Widemann, Brigitte C
BACKGROUND:Understanding the natural history of non-malignant peripheral nerve sheath tumors (PNSTs) in neurofibromatosis type 1 (NF1) is critical to optimal clinical care and the development of meaningful clinical trials. METHODS:We longitudinally analyzed growth of plexiform neurofibromas (PNs) and of PNSTs with distinct nodular appearance (distinct nodular lesions/DNLs) using volumetric MRI analysis in patients enrolled on a natural history study (NCT00924196). RESULTS:DNLs were observed in 58/122 (45.6%) patients (median 2 DNLs/patient). In DNLs that developed during follow-up, median age of development was 17 years. A moderate negative correlation was observed between the estimated PN growth rate and patients' age at initial MRI (Spearman's r (95% CI): -0.60 (-0.73, -0.43), n=70); whereas only a weak correlation was observed for DNLs (Spearman's r (95% CI): -0.25 (-0.47, 0.004); n=61). We observed a moderate negative correlation between tumor growth rate and baseline tumor volume for PNs and DNLs (Spearman's r (95% CI): -0.52 (-0.67, -0.32)) and -0.61 (-0.75, -0.42) respectively). Spontaneous tumor volume reduction was observed in 10 PNs and 7 DNLs (median decrease rate 3.6%/year and 7.3%/year respectively). CONCLUSION/CONCLUSIONS:We corroborate previously described findings that most rapidly growing PNs are observed in young children. DNLs tend to develop later in life and their growth is minimally age related. Distinct growth characteristics of PNs and DNLs suggest that these lesions have a different biology and may require different clinical management and clinical trial design. In a subset of PNs and DNLs, slow spontaneous regression in tumor volume was seen.
PMID: 32152628
ISSN: 1523-5866
CID: 4348802

A Systematic Review of Pediatric Phase I Trials in Oncology: Toxicity and Outcomes in the Era of Targeted Therapies

Cohen, Julia W; Akshintala, Srivandana; Kane, Eli; Gnanapragasam, Helen; Widemann, Brigitte C; Steinberg, Seth M; Shah, Nirali N
BACKGROUND:Pediatric phase I oncology trials have historically focused on safety and toxicity, with objective response rates (ORRs) <10%. Recently, with an emphasis on targeted approaches, response rates may have changed. We analyzed outcomes of recent phase I pediatric oncology trials. MATERIALS AND METHODS/METHODS:This was a systematic review of phase I pediatric oncology trials published in 2012-2017, identified through PubMed and EMBASE searches conducted on March 14, 2018. Selection criteria included full-text articles with a pediatric population, cancer diagnosis, and a dose escalation schema. Each publication was evaluated for patient characteristics, therapy type, trial design, toxicity, and response. RESULTS:Of 3,431 citations, 109 studies (2,713 patients) met eligibility criteria. Of these, 78 (72%) trials incorporated targeted therapies. Median age at enrollment/trial was 11 years (range 3-21 years). There were 2,471 patients (91%) evaluable for toxicity, of whom 300 (12.1%) experienced dose-limiting toxicity (DLT). Of 2,143 patients evaluable for response, 327 (15.3%) demonstrated an objective response. Forty-three (39%) trials had no objective responses. Nineteen trials (17%) had an ORR >25%, of which 11 were targeted trials and 8 were combination cytotoxic trials. Targeted trials demonstrated a lower DLT rate compared with cytotoxic trials (10.6% vs. 14.7%; p = .003) with similar ORRs (15.0% vs. 15.9%; p = .58). CONCLUSION/CONCLUSIONS:Pediatric oncology phase I trials in the current treatment era have an acceptable DLT rate and a pooled ORR of 15.3%. A subset of trials with target-specific enrollment or combination cytotoxic therapies showed high response rates, highlighting the importance of these strategies in early phase trials. IMPLICATIONS FOR PRACTICE/CONCLUSIONS:Enrollment in phase I oncology trials is crucial for development of novel therapies. This systematic review of phase I pediatric oncology trials provides an assessment of outcomes of phase I trials in children, with a specific focus on the impact of targeted therapies. These data may aid in evaluating the landscape of current phase I options for patients and enable more informed communication regarding risk and benefit of phase I clinical trial participation. The results also suggest that, in the current treatment era, there is a rationale to increase earlier access to targeted therapy trials for this refractory patient population.
PMID: 31943534
ISSN: 1549-490x
CID: 4263742

Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study

Castinetti, Frederic; Waguespack, Steven G; Machens, Andreas; Uchino, Shinya; Lazaar, Kornelia; Sanso, Gabriella; Else, Tobias; Dvorakova, Sarka; Qi, Xiao Ping; Elisei, Rossella; Maia, Ana Luisa; Glod, John; Lourenço, Delmar Muniz; Valdes, Nuria; Mathiesen, Jes; Wohllk, Nelson; Bandgar, Tushar R; Drui, Delphine; Korbonits, Marta; Druce, Maralyn R; Brain, Caroline; Kurzawinski, Tom; Patocs, Atila; Bugalho, Maria Joao; Lacroix, Andre; Caron, Philippe; Fainstein-Day, Patricia; Borson Chazot, Francoise; Klein, Marc; Links, Thera P; Letizia, Claudio; Fugazzola, Laura; Chabre, Olivier; Canu, Letizia; Cohen, Regis; Tabarin, Antoine; Spehar Uroic, Anita; Maiter, Dominique; Laboureau, Sandrine; Mian, Caterina; Peczkowska, Mariola; Sebag, Frederic; Brue, Thierry; Mirebeau-Prunier, Delphine; Leclerc, Laurence; Bausch, Birke; Berdelou, Amandine; Sukurai, Akihiro; Vlcek, Petr; Krajewska, Jolanta; Barontini, Marta; Vaz Ferreira Vargas, Carla; Valerio, Laura; Ceolin, Lucieli; Akshintala, Srivandana; Hoff, Ana; Godballe, Christian; Jarzab, Barbara; Jimenez, Camilo; Eng, Charis; Imai, Tsuneo; Schlumberger, Martin; Grubbs, Elizabeth; Dralle, Henning; Neumann, Hartmut P; Baudin, Eric
BACKGROUND:Multiple endocrine neoplasia type 2B is a rare syndrome caused mainly by Met918Thr germline RET mutation, and characterised by medullary thyroid carcinoma, phaeochromocytoma, and extra-endocrine features. Data are scarce on the natural history of multiple endocrine neoplasia type 2B. We aimed to advance understanding of the phenotype and natural history of multiple endocrine neoplasia type 2B, to increase awareness and improve detection. METHODS:This study was a retrospective, multicentre, international study in patients carrying the Met918Thr RET variant with no age restrictions. The study was done with registry data from 48 centres globally. Data from patients followed-up from 1970 to 2016 were retrieved from May 1, 2016, to May 31, 2018. Our primary objectives were to determine overall survival, and medullary thyroid carcinoma-specific survival based on whether the patient had undergone early thyroidectomy before the age of 1 year. We also assessed remission of medullary thyroid carcinoma, incidence and treatment of phaeochromocytoma, and the penetrance of extra-endocrine features. FINDINGS/RESULTS:345 patients were included, of whom 338 (98%) had a thyroidectomy. 71 patients (21%) of the total cohort died at a median age of 25 years (range <1-59). Thyroidectomy was done before the age of 1 year in 20 patients, which led to long-term remission (ie, undetectable calcitonin level) in 15 (83%) of 18 individuals (2 patients died of causes unrelated to medullary thyroid carcinoma). Medullary thyroid carcinoma-specific survival curves did not show any significant difference between patients who had thyroidectomy before or after 1 year (comparison of survival curves by log-rank test: p=0·2; hazard ratio 0·35; 95% CI 0.07-1.74). However, there was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). There was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). In the other 318 patients who underwent thyroidectomy after 1 year of age, biochemical and structural remission was obtained in 47 (15%) of 318 individuals. Bilateral phaeochromocytoma was diagnosed in 156 (50%) of 313 patients by 28 years of age. Adrenal-sparing surgery was done in 31 patients: three (10%) of 31 patients had long-term recurrence, while normal adrenal function was obtained in 16 (62%) patients. All patients with available data (n=287) had at least one extra-endocrine feature, including 106 (56%) of 190 patients showing marfanoid body habitus, mucosal neuromas, and gastrointestinal signs. INTERPRETATION/CONCLUSIONS:Thyroidectomy done at no later than 1 year of age is associated with a high probability of cure. The reality is that the majority of children with the syndrome will be diagnosed after this recommended age. Adrenal-sparing surgery is feasible in multiple endocrine neoplasia type 2B and affords a good chance for normal adrenal function. To improve the prognosis of such patients, it is imperative that every health-care provider be aware of the extra-endocrine signs and the natural history of this rare syndrome. The implications of this research include increasing awareness of the extra-endocrine symptoms and also recommendations for thyroidectomy before the age of 1 year. FUNDING/BACKGROUND:None.
PMID: 30660595
ISSN: 2213-8595
CID: 3610192

Pheochromocytoma in children and adolescents with multiple endocrine neoplasia type 2B

Makri, Angeliki; Akshintala, Srivandana; Derse-Anthony, Claudia; Del Rivero, Jaydira; Widemann, Brigitte; Stratakis, Constantine A; Glod, John; Lodish, Maya
Background/UNASSIGNED:Multiple endocrine neoplasia type 2B (MEN2B) is characterized by early-onset medullary thyroid cancer (MTC) in virtually all cases and a 50% lifetime risk of pheochromocytoma (PHEO) development. The literature on PHEO in patients with MEN2B is limited with most data being reported from adult studies that primarily address MEN2A. Aim/UNASSIGNED:The aim of the current study is to describe PHEO development in a cohort of pediatric patients with MEN2B. Design/UNASSIGNED:Retrospective chart review of patients with MEN2B evaluated at the NIH in the period between July 2007 and February 2018. Results/UNASSIGNED:A total of 38 patients were identified (21 males and 17 females). Mean age at MEN2B diagnosis was 10.6 ± 3.9 years. Eight patients (21%) developed PHEO in the course of follow-up to date, all of whom were sporadic cases with the classic M918T RET mutation. PHEO was diagnosed based on biochemical and/or imaging screening studies in 5 patients while 3 patients presented with symptomatology of excess catecholamines. PHEO was diagnosed at a mean age 15.2 ± 4.6 (range 10 - 25) years and 4.0 ± 3.3 yrs after MEN2B diagnosis. Only one patient was diagnosed with PHEO as the initial manifestation of MEN2B after she presented with hypertension and secondary amenorrhea. Conclusion/UNASSIGNED:Undiagnosed PHEO can be associated with significant morbidity. Current ATA guidelines recommend PHEO screening starting at age 11 for the high-/highest risk group. The youngest patient diagnosed with PHEO in our cohort was an asymptomatic 10 years-old, suggesting that PHEO development may begin before the screening -recommended age of 11, though remains clinically undetectable and thus the current screening guidelines seem appropriate.
PMID: 30113649
ISSN: 1945-7197
CID: 3241362

A PHASE 0 PHARMACODYNAMIC AND PHARMACOKINETIC STUDY OF EVEROLIMUS IN VESTIBULAR SCHWANNOMA (VS) AND MENINGIOMA PATIENTS [Meeting Abstract]

Karajannis, Matthias; Wang, Shiyang; Goldberg, Judith; Roland, Thomas; Sen, Chandranath; Placantonakis, Dimitris; Golfinos, John; Allen, Jeffrey; Dunbar, Erin; Plotkin, Scott; Akshintala, Srivandana; Schneider, Robert; Deng, Jingjing; Neubert, Thomas; Giancotti, Filippo; Blakeley, Jaishri
ISI:000473243700215
ISSN: 1522-8517
CID: 4511782

A PHASE 0 PHARMACODYNAMIC AND PHARMACOKINETIC STUDY OF EVEROLIMUS IN VESTIBULAR SCHWANNOMA (VS) AND MENINGIOMA PATIENTS [Meeting Abstract]

Karajannis, Matthias; Goldberg, Judith; Roland, J. Thomas; Sen, Chandranath; Placantonakis, Dimitris; Golfinos, John; Allen, Jeffrey; Dunbar, Erin; Plotkin, Scott; Akshintala, Srivandana; Schneider, Robert; Deng, Jingjing; Neubert, Thomas A.; Giancotti, Filippo; Zagzag, David; Blakeley, Jaishri O.
ISI:000509478700053
ISSN: 1522-8517
CID: 4511792