Multicenter phase II study of temozolomide and myeloablative chemotherapy with autologous stem cell transplant for newly diagnosed anaplastic oligodendroglioma

Alissa A Thomas, Lauren E Abrey, Robert Terziev, Jeffrey Raizer, Nina L Martinez, Peter Forsyth, Nina Paleologos, Matthew Matasar, Craig S Sauter, Craig Moskowitz, Stephen D Nimer, Lisa M DeAngelis, Thomas Kaley, Sean Grimm, David N Louis, J Gregory Cairncross, Katherine S Panageas, Samuel Briggs, Geraldine Faivre, Nimish A Mohile, Jayesh Mehta, Philip Jonsson, Debyani Chakravarty, Jianjiong Gao, Nikolaus Schultz, Cameron W Brennan, Jason T Huse, Antonio Omuro, Alissa A Thomas, Lauren E Abrey, Robert Terziev, Jeffrey Raizer, Nina L Martinez, Peter Forsyth, Nina Paleologos, Matthew Matasar, Craig S Sauter, Craig Moskowitz, Stephen D Nimer, Lisa M DeAngelis, Thomas Kaley, Sean Grimm, David N Louis, J Gregory Cairncross, Katherine S Panageas, Samuel Briggs, Geraldine Faivre, Nimish A Mohile, Jayesh Mehta, Philip Jonsson, Debyani Chakravarty, Jianjiong Gao, Nikolaus Schultz, Cameron W Brennan, Jason T Huse, Antonio Omuro

Abstract

Background: Anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) are chemotherapy-sensitive tumors with prolonged survival after radiochemotherapy. We report a prospective trial using induction temozolomide (TMZ) followed by myeloablative high-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) as a potential strategy to defer radiotherapy.

Methods: Patients with AO/AOA received 6 cycles of TMZ (200 mg/m2 × 5/28 day). Responding patients were eligible for HDC (thiotepa 250 mg/m2/day × 3 days, then busulfan 3.2 mg/kg/day × 3 days), followed by ASCT. Genomic characterization was performed using next-generation sequencing.

Results: Forty-one patients were enrolled; 85% had 1p/19q codeleted tumors. After induction, 26 patients were eligible for HDC-ASCT and 21 agreed to proceed. There were no unexpected adverse events or toxic deaths. After median follow-up of 66 months, 2-year progression-free survival (PFS) for transplanted patients was 86%, 5-year PFS 60%, and no patient has died. Among all 1p/19q codeleted patients (N = 33), 5-year PFS was 50% and 5-year overall survival (OS) 93%, with median time to radiotherapy not reached. Next-generation sequencing disclosed typical oligodendroglioma-related mutations, including IDH1, TERT, CIC, and FUBP1 mutations in 1p/19q codeleted patients, and glioblastoma-like signatures in 1p/19q intact patients. Aside from IDH1, potentially oncogenic/actionable mutations were variable, depicting wide molecular heterogeneity within oligodendroglial tumors.

Conclusions: TMZ followed by HDC-ASCT can be safely administered to patients with newly diagnosed 1p/19q codeleted AO. This strategy was associated with promising PFS and OS, suggesting that a chemotherapy-based approach may delay the need for radiotherapy and radiation-related toxicities. Raw data for further genomic and meta-analyses are publicly available at http://cbioportal.org/study?id=odg_msk_2017, accessed 6 January 2017.

Clinicaltrials.gov registry: NCT00588523.

Keywords: 1p/19q codeletion; anaplastic oligodendroglioma; autologous stem cell transplant; temozolomide.

© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Figures

Fig. 1
Fig. 1
Kaplan–Meier survival curves of PFS and OS in transplanted patients (N = 21; A and B), in the intent-to-treat population (all patients, N = 41, C and D), and in all patients with 1p/19q codeletion (N = 33, E and F).
Fig. 2
Fig. 2
Distribution of mutations and copy number alterations as determined by next-generation sequencing utilizing a panel of 410 cancer-related genes (1p/19q loss shown determined by FISH).

References

    1. Macdonald DR, Gaspar LE, Cairncross JG. Successful chemotherapy for newly diagnosed aggressive oligodendroglioma. Ann Neurol. 1990;27(5):573–574.
    1. Cairncross JG, Macdonald DR. Chemotherapy for oligodendroglioma. Progress report. Arch Neurol. 1991;48(2):225–227.
    1. Abrey LE, Childs BH, Paleologos N et al. . High-dose chemotherapy with stem cell rescue as initial therapy for anaplastic oligodendroglioma: long-term follow-up. Neuro Oncol. 2006;8(2):183–188.
    1. Walker MD, Alexander E Jr, Hunt WE et al. . Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg. 1978;49(3):333–343.
    1. Cairncross G, Wang M, Shaw E et al. . Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013;31(3):337–343.
    1. van den Bent MJ, Brandes AA, Taphoorn MJ et al. . Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013;31(3):344–350.
    1. Mohile NA, Forsyth P, Stewart D et al. . A phase II study of intensified chemotherapy alone as initial treatment for newly diagnosed anaplastic oligodendroglioma: an interim analysis. J Neurooncol. 2008;89(2):187–193.
    1. Abrey LE, Childs BH, Paleologos N et al. . High-dose chemotherapy with stem cell rescue as initial therapy for anaplastic oligodendroglioma. J Neurooncol. 2003;65(2):127–134.
    1. Dummer W, Niethammer AG, Baccala R et al. . T cell homeostatic proliferation elicits effective antitumor autoimmunity. J Clin Invest. 2002;110(2):185–192.
    1. Sampson JH, Aldape KD, Archer GE et al. . Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol. 2011;13(3):324–333.
    1. Gan HK, Rosenthal MA, Dowling A et al. . A phase II trial of primary temozolomide in patients with grade III oligodendroglial brain tumors. Neuro Oncol. 2010;12(5):500–507.
    1. Taliansky-Aronov A, Bokstein F, Lavon I, Siegal T. Temozolomide treatment for newly diagnosed anaplastic oligodendrogliomas: a clinical efficacy trial. J Neurooncol. 2006;79(2):153–157.
    1. Mikkelsen T, Doyle T, Anderson J et al. . Temozolomide single-agent chemotherapy for newly diagnosed anaplastic oligodendroglioma. J Neurooncol. 2009;92(1):57–63.
    1. Cheng DT, Mitchell TN, Zehir A et al. . Memorial sloan kettering-integrated mutation profiling of actionable cancer targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J Mol Diagn. 2015;17(3):251–264.
    1. Cairncross G, Macdonald D, Ludwin S et al. . Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1994;12(10):2013–2021.
    1. Chamberlain MC, Kormanik PA. Salvage chemotherapy with paclitaxel for recurrent oligodendrogliomas. J Clin Oncol. 1997;15(12):3427–3432.
    1. Friedman HS, Lovell S, Rasheed K, Friedman AH. Treatment of adults with progressive oligodendroglioma with carboplatin (CBDCA): preliminary results. Writing Committee for The Brain Tumor Center at Duke. Med Pediatr Oncol. 1998;31(1):16–18.
    1. Wick W, Hartmann C, Engel C et al. . NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009;27(35):5874–5880.
    1. Louis DN, Perry A, Reifenberger G et al. . The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803–820.
    1. Brat DJ, Verhaak RG, Aldape KD et al. ; The Cancer Genome Atlas Research Network. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med. 2015;372(26):2481–2498.
    1. Brennan CW, Verhaak RG, McKenna A et al. ; TCGA Research Network. The somatic genomic landscape of glioblastoma. Cell. 2013;155(2):462–477.
    1. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061–1068.
    1. Eckel-Passow JE, Lachance DH, Molinaro AM et al. . Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med. 2015;372(26):2499–2508.
    1. Dubbink HJ, Atmodimedjo PN, Kros JM et al. . Molecular classification of anaplastic oligodendroglioma using next-generation sequencing: a report of the prospective randomized EORTC Brain Tumor Group 26951 phase III trial. Neuro Oncol. 2016;18(3):388–400.
    1. Dubbink HJ, Atmodimedjo PN, van Marion R et al. . Diagnostic detection of allelic losses and imbalances by next-generation sequencing: 1p/19q co-deletion analysis of gliomas. J Mol Diagn. 2016;18(5):775–786.
    1. Wick W, Roth P, Hartmann C et al. ; Neurooncology Working Group (NOA) of the German Cancer Society. Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol. 2016;18(11):1529–1537.
    1. Jaeckle K, Vogelbaum M, Ballman K et al. . CODEL (Alliance-N0577; EORTC-26081/22086; NRG-1071; NCIC-CEC-2): Phase III Randomized Study of RT vs. RT+TMZ vs. TMZ for Newly Diagnosed 1p/19q-Codeleted Anaplastic Oligodendroglial Tumors. Analysis of Patients Treated on the Original Protocol Design (PL02.005). Neurology. 2016;88(16):Suppl PL02.005.
    1. Cerami E, Gao J, Dogrusoz U et al. . The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–404.
    1. Gao J, Aksoy BA, Dogrusoz U et al. . Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):pl1.
    1. Ahluwalia MS, Xie H, Dahiya S et al. . Efficacy and patient-reported outcomes with dose-intense temozolomide in patients with newly diagnosed pure and mixed anaplastic oligodendroglioma: a phase II multicenter study. J Neurooncol. 2015;122(1):111–119.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다