Abstract
Introduction
Diffuse midline gliomas (DMG) with the H3 K27M-mutation are a well-described entity with most DMG harboring this mutation, with notable heterogeneity in adults. No therapy has been proven to improve survival in this tumor type. Panobinostat is a histone deacetylase inhibitor that may have therapeutic benefit.
Methods
We report our retrospective experience with use of panobinostat in adults (> 18 years) with H3 K27M-mutant DMG treated at Mayo Clinic (Rochester) from January 2016 to August 2020, with follow-up until October 2021. Survival was calculated using the Kaplan–Meier method.
Results
4 patients with H3 K27M-mutant glioma were treated with panobinostat as compassionate use. Patients had a median age of 40 years (range 22–62 years) and 2 were female. Tumor location was midline for all patients, spinal cord (n = 2), brainstem (n = 1), and thalamus (n = 1). All tumors were IDH1/IDH2 wildtype. 3 patients received radiotherapy followed by adjuvant panobinostat. All patients had no other pharmacologic therapy utilized prior to or during panobinostat therapy aside from concurrent dexamethasone utilized in 3 patients. No patient experienced a grade 2 or higher (per CTCAE grade) adverse effect. The median overall survival was 42 months, median progression free survival of 19 months, 2 patients were alive at last follow up (both with spinal cord tumors and received radiation). The best response was stable disease in 2 patients and a partial response in 1 patient.
Conclusions
This is the first report of clinical outcomes of panobinostat in adults with H3 K27M-mutant DMG. We showed that it is well-tolerated at the dosage schedule that we describe, with no serious adverse effects throughout the study period.
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References
Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng H, Pfister SM, Reifenberger G (2021) The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro-Oncology 23:1231–1251
Louis DN, Giannini C, Capper D, Paulus W, Figarella-Branger D, Lopes MB, Batchelor TT, Cairncross JG, van den Bent M, Wick W (2018) cIMPACT-NOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant. Acta Neuropathol 135:639–642
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820. https://doi.org/10.1007/s00401-016-1545-1
Solomon DA, Wood MD, Tihan T, Bollen AW, Gupta N, Phillips JJ, Perry A (2016) Diffuse midline gliomas with histone H3-K27M mutation: a series of 47 cases assessing the spectrum of morphologic variation and associated genetic alterations. Brain Pathol 26:569–580
Sievers P, Sill M, Schrimpf D, Stichel D, Reuss DE, Sturm D, Hench J, Frank S, Krskova L, Vicha A (2021) A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR. Neuro-Oncology 23:34–43
Meyronet D, Esteban-Mader M, Bonnet C, Joly M-O, Uro-Coste E, Amiel-Benouaich A, Forest F, Rousselot-Denis C, Burel-Vandenbos F, Bourg V (2017) Characteristics of H3 K27M-mutant gliomas in adults. Neuro-Oncology 19:1127–1134
Schreck K, Ranjan S, Skorupan N, Holdhoff M, Ames H (2019) Incidence and natural history of H3 K27M-mutated midline gliomas in adults. Neurology 92(S30):001
Schreck KC, Ranjan S, Skorupan N, Bettegowda C, Eberhart CG, Ames HM, Holdhoff M (2019) Incidence and clinicopathologic features of H3 K27M mutations in adults with radiographically-determined midline gliomas. J Neurooncol 143:87–93. https://doi.org/10.1007/s11060-019-03134-x
Kleinschmidt-DeMasters BK, Levy JMM (2018) H3 K27M-mutant gliomas in adults vs. children share similar histological features and adverse prognosis. Clin Neuropathol 37:53
Buerki R, Lapointe S, Solomon D, Phillips J, Perry A, Villaneuva-Meyer J, Molinaro A, Bush NAO, Taylor J, Butowski N (2019) Clinical and pathological characteristics of 52 adults with H3 K27M-mutant diffuse midline gliomas at UCSF. 92 (Supplement S14.004)
Daoud EV, Rajaram V, Cai C, Oberle RJ, Martin GR, Raisanen JM, White CL III, Foong C, Mickey BE, Pan E (2018) Adult brainstem gliomas with H3K27M mutation: radiology, pathology, and prognosis. J Neuropathol Exp Neurol 77:302–311
Eschbacher KL, Ida CM, Johnson DR, Alvi MA, Jenkins SM, Ruff MW, Kerezoudis P, Neth BJ, Pasion RM, Daniels DJ, Kizilbash SH, Raghunathan A (2021) Diffuse gliomas of the brainstem and cerebellum in adults show molecular heterogeneity. Am J Surg Pathol 45:1082–1090. https://doi.org/10.1097/pas.0000000000001690
Schulte JD, Buerki RA, Lapointe S, Molinaro AM, Zhang Y, Villanueva-Meyer JE, Perry A, Phillips JJ, Tihan T, Bollen AW (2020) Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults. Neuro-Oncol Adv 2:vdaa142
Yekula A, Gupta M, Coley N (2020) Adult H3K27M-mutant diffuse midline glioma with gliomatosis cerebri growth pattern: case report and review of the literature. Int J Surg Case Rep 68:124–128
Low JT, Wang S-H, Peters KB (2021) Diffuse midline glioma with H3 K27M-mutation in an 83-year-old woman. CNS Oncol. https://doi.org/10.2217/cns-2020-0030
Wang Y, Feng L-l, Ji P-g, Liu J-h, Guo S-c, Zhai Y-l, Sankey EW, Wang Y, Xue Y-r, Wang N, Lou M, Xu M, Chao M, Gao G-D, Qu Y, Gong L, Wang L (2021) Clinical features and molecular markers on diffuse midline gliomas With H3K27M mutations: a 43 cases retrospective cohort study. Front Oncol. https://doi.org/10.3389/fonc.2020.602553
Takahashi M, Tomita Y, Yamada SM, Yamazaki K, Yokoo H, Aso T, Kawamoto M (2021) Cerebellar high-grade glioma with H3 K27M mutation: illustrative case. J Neurosurg. https://doi.org/10.3171/case20112
He P, Chen W, Qiu XX, Xi YB, Guan H, Xia J (2019) A rare high-grade glioma with a histone H3 K27M mutation in the hypothalamus of an adult patient. World Neurosurg 128:527–531. https://doi.org/10.1016/j.wneu.2019.04.172
Bechet D, Gielen GG, Korshunov A, Pfister SM, Rousso C, Faury D, Fiset P-O, Benlimane N, Lewis PW, Lu C (2014) Specific detection of methionine 27 mutation in histone 3 variants (H3K27M) in fixed tissue from high-grade astrocytomas. Acta Neuropathol 128:733–741
Wierzbicki K, Ravi K, Franson A, Bruzek A, Cantor E, Harris M, Homan MJ, Marini BL, Kawakibi AR, Ravindran R (2020) Targeting and therapeutic monitoring of H3K27M-mutant glioma. Curr Oncol Rep 22:1–9
Haag D, Mack N, Goncalves B, da Silva P, Statz B, Clark J, Tanabe K, Sharma T, Jäger N, Jones DTW, Kawauchi D, Wernig M, Pfister SM (2021) H3.3-K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model. Cancer Cell 39:407-422.e413. https://doi.org/10.1016/j.ccell.2021.01.005
Cooney TM, Lubanszky E, Prasad R, Hawkins C, Mueller S (2020) Diffuse midline glioma: review of epigenetics. J Neuro-Oncol. https://doi.org/10.1007/s11060-020-03553-1
Hennika T, Hu G, Olaciregui NG, Barton KL, Ehteda A, Chitranjan A, Chang C, Gifford AJ, Tsoli M, Ziegler DS (2017) Pre-clinical study of panobinostat in xenograft and genetically engineered murine diffuse intrinsic pontine glioma models. PLoS ONE 12:e0169485
Atadja P (2009) Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett 280:233–241
Mueller S, Jain P, Liang WS, Kilburn L, Kline C, Gupta N, Panditharatna E, Magge SN, Zhang B, Zhu Y, Crawford JR, Banerjee A, Nazemi K, Packer RJ, Petritsch CK, Truffaux N, Roos A, Nasser S, Phillips JJ, Solomon D, Molinaro A, Waanders AJ, Byron SA, Berens ME, Kuhn J, Nazarian J, Prados M, Resnick AC (2019) A pilot precision medicine trial for children with diffuse intrinsic pontine glioma-PNOC003: a report from the Pacific Pediatric Neuro-Oncology Consortium. Int J Cancer 145:1889–1901. https://doi.org/10.1002/ijc.32258
Lee EQ, Reardon DA, Schiff D, Drappatz J, Muzikansky A, Grimm SA, Norden AD, Nayak L, Beroukhim R, Rinne ML (2015) Phase II study of panobinostat in combination with bevacizumab for recurrent glioblastoma and anaplastic glioma. Neuro-Oncology 17:862–867
Fenichel MP (2015) FDA approves new agent for multiple myeloma. JNCI 107:djv165
FDA (2015) Highlights of prescribing information: FARYDAK® (panobinostat) capsules, for oral use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205353s000lbl.pdf. Accessed 9 Oct 2021
Roux A, Pallud J, Saffroy R, Edjlali-Goujon M, Debily M-A, Boddaert N, Sanson M, Puget S, Knafo S, Adam C (2020) High-grade gliomas in adolescents and young adults highlight histomolecular differences from their adult and pediatric counterparts. Neuro Oncol 22:1190–1202
Tosi U, Kommidi H, Adeuyan O, Guo H, Maachani UB, Chen N, Su T, Zhang G, Pisapia DJ, Dahmane N (2020) PET, image-guided HDAC inhibition of pediatric diffuse midline glioma improves survival in murine models. Sci Adv. https://doi.org/10.1126/sciadv.abb4105
Lin GL, Wilson KM, Ceribelli M, Stanton BZ, Woo PJ, Kreimer S, Qin EY, Zhang X, Lennon J, Nagaraja S (2019) Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aaw0064
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Neth, B.J., Balakrishnan, S.N., Carabenciov, I.D. et al. Panobinostat in adults with H3 K27M-mutant diffuse midline glioma: a single-center experience. J Neurooncol 157, 91–100 (2022). https://doi.org/10.1007/s11060-022-03950-8
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DOI: https://doi.org/10.1007/s11060-022-03950-8