Neurofibroma / Nerve Sheath Tumor

Transcription

1 Dermal 95% Neurofibroma / Nerve Sheath Tumor Plexiform (PN) 25-40% Atypical (ANF) Unknown? MPNST 15.8% Appearance, pruritus Appearance, pain, function loss, Malignant transformation Loss of NF1 + CDKN2A/B + PRC2, P53, others

2 Whole Body MRI: Identification of Distinct Nodular Lesions Round/oval, well demarcated, 3 cm, within or outside PN Lack the central dot sign characteristic of PN FDG avid in comparison to the surrounding PN Growth rate exceeds PN growth rate. Age 2 Age 9 Age 12

3 Development of Atypical Neurofibroma in Plexiform Neurofibroma Girl with NF1 and Neck/Chest PN Neurofibroma ANF Encapsulated lesion resected, no recurrence

4 Relationship of Growth Rate and Age Srivandana Akshintala PN grow most rapidly in young patients. PN growth 20% per year is rare in 15 year-old patients. Nodular lesions grow independently of age. Nodular lesions are not observed in very young children. Nodular lesions may have different biology: Atypical neurofibromas (CDKN2A/B deletion)

5 Imaging: Eva Dombi Jeffrey Solomon Research nurse / NP / PCC / MD: Trish Whitcomb, Marielle Holmblad Anne Goodwin Amanda Carbonell Andrea Baldwin, Joanne Derdak Kara Heisey Andrea Gross, Diana Bradford Christine Higham Participating sites/collaborators Brian Weiss Michael Fisher AeRang Kim Doug Stewart Karlyne Reilly Eric Legius Ros Ferner Acknowledgements CTEP: John Wright, Austin Doyle FDA AstraZeneca REiNS: Scott Plotkin Preclinical Trials Nancy Ratner Wade Clapp SARC DoD NF Clinical Trials Consortium Funding: DoD, CTF NTAP: Jaishri Blakeley Statistical support: Seth Steinberg Patient and families

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7 Phase II Trial of Imatinib Eligibility: NF y/o with clinically significant PN Treatment: Imatinib 220 mg BID for children, 400 mg BID for adults Primary endpoint: Volumetric response ( 20% decrease in PN volume) Results: Response rate: 6 of 36 pts had OR (17%) 6 of 23 pts (26%) treated 6 months had OR Most common AEs: Rash (6), edema (6) neutropenia (2) AST (1) K. Robertson D. Wade Clapp. Lancet Oncology 2012

8 Appearance Improvement 10 y/o with right neck plexiform neurofibroma Baseline Pre cycle 5 Pre cycle 10 Pre cycle 15

9 Management of Atypical Neurofibromas 10 year-old boy with asymptomatic, newly diagnosed PN Inguinal Paraspinal Pathology ANF NF Germline NF1 Splicing c.288+2t>g Somatic Frameshift p.i1402fs CDKN2A/B Het. loss 9pter-p13.3 Het. loss 9pter p-21.3

10 Malignant Peripheral Nerve SheathTumor (MPNST) Aggressive soft tissue sarcoma (STS), 50% in neurofibromatosis type 1 (NF1) Complete surgical resection is required for cure No effective medical therapy, no improvement in outcome MPNST State of the Science: Outlining a Research Agenda for the Future - Oct 5-7, 2016 Presented by:

11 Histopathologic Evaluation of ANF and their Transformation into MPNST Expert Pathology Consensus Review NCI/CTF: MPNST State of the Science Conference 2016 M. Miettinen, C. Antonescu, C. Fletcher, A. Lazar, M. Quezado, A. Stemmer-Rachamimov, Arie Perry Diagnosis Neurofibroma with atypia ( Ancient NF ) Cellular NF Atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) MPNST, low grade MPNST, high grade Proposed Definition NF with atypia alone, most commonly manifesting as scattered bizarre nuclei NF with hypercellularity, but retained NF architecture and <1 mf/50 HPF Schwann cell neoplasm with at least 2 of 4 features: cytologic atypia, loss of neurofibroma architecture, hypercellularity, mitotic index >1/50 HPF and <3/10 HPF Features of ANNUBP, but with mitotic index of 3-9/10 HPF and no necrosis MPNST with at least 10 mf/10 HPF or 3-9 mf/10 HPF combined with necrosis Miettinen M Perry A., Human Pathology 2017

12 Malignant Peripheral Nerve Sheath Tumor (MPNST) Aggressive soft tissue sarcoma (STS) 4% of all STS, 50% in neurofibromatosis type 1 (NF1) Lifetime incidence of MPNST in NF1 15.8% Risk factors: Whole gene deletion, prior radiation therapy, ANF, large PN tumor burden Development in preexisting PN and ANF in NF1 LOF somatic alterations in PRC2 core components: EED and SUZ12 92% of Sporadic MPNSTs 70% NF1-associated MPNSTs 90% Radiotherapy-associated MPNSTs Clinical signs and symptoms of PN and MPNST overlap Complete surgical resection with negative margins required for cure No effective medical therapy No improvement in outcome

13 Role of Chemotherapy in MPNST Response to standard sarcoma chemotherapy in sporadic and NF1 MPNST Variable N 5-Year OS (%) Chemotherapy Response (%) Reference NF No NF NF No NF NF No NF NF No NF Carli, 2005 JCO Ferrari, 2011 European J of Cancer Hirbe, 2017 Sarcoma Higham, 2017 Sarcoma

14 Phase II Trial of Chemotherapy for MPNST NCI, SARC, NF1 Centers NF1 IA x 2 IE x 2 MPNST I - Ifosfamide A - Adriamycin E - Etoposide Response Evaluation Local Control Chemotherapy 8 cycles total Sporadic IA x 2 IE x 2 PET 3D MRI MRI PET 3D MRI Surgery XRT Eight chemotherapy cycles total: Doxorubicin: 37.5 mg/m 2 days 1 and 2 (cumulative 300 mg/m 2 ) Ifosfamide: 1,800 mg/m 2 days 1-5 (cumulative 72,000 mg/m 2 ) Etoposide: 100 mg/m 2 days 1-5 (cumulative 2,000 mg/m 2 )

15 SARC006: Response Evaluation Characteristics NF1 Sporadic Evaluable post cycle Complete Response - - Partial Response 5 4 Stable Disease 20 4 Progressive Diasease 3 1 CR/PR rate (%)

16 Response after 4 Cycles (2 IA, 2IE) and 2 Cycles (IA) Sporadic MPNST NF1 MPNST % Change from Baseline % Change from Baseline % Change from Baseline % Change from Baseline Higham C Widemann B. Sarcoma, 2017

17 Phase II Trials with Targeted Agents for Refractory MPNST Target Agent Patients (N) Age (yr) Outcome Erlotinib EGFR 20 (10 NF1) 18 No PR, 18/20 PD after 2 cycles Sorafenib Imatinib Dasatinib Bevacizumab, Everolimus Raf, VEGFR, PDGFR, C-KIT C-KIT, PDGFR VEGFR C-KIT, SRC Angiogenesis mtor No PR, PFS 1.7 mo, SD n= No PR or SD No PR, no SD at 4 cycles 25 (17 NF1) 18 No PR, 3 pts. SD at cycle 4 MLN8237 (Alisertib) Aurora Kinase A No PR, 12 week PFS 60% Ganetespib Sirolimus HSP90 mtor 10 (5 NF1) 16 No PR, 1 SD at cycle 4 (RECIST) Clinical benefit in MPNST: Complete response, partial response, stable disease at 4 cycles

18 Slow Spontaneous Volume Decrease in 10 of 112 PN 20% volume decrease over 4 years Pt # Decrease from max. vol. (%) Follow-up Duration (years) Decrease / year (%) Age at max. vol. (years) Median Range : 674 ml 2007: 1420 ml 2010: 1347 ml 2012: Not measurable

19 PFS (%) Progression Free Survival Phase A : 10.6 months : 19.2 months Log-rank p-value one-sided: TTP (months)

20 PFS (%) Progression Free Survival Phase B From start of treatment on phase B : 14.5 months : 13.3 months Log-rank p-value one-sided: 0.15 TTP (months)