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

Authors

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

Doi

10.1093/neuonc/nox086

PMID: 28472509 · DOI: 10.1093/neuonc/nox086 · Journal: Neuro-Oncology (2017)

TL;DR

Thomas et al. report a multicenter phase II trial (NCT00588523) testing whether single-agent temozolomide (TMZ) induction followed by myeloablative high-dose thiotepa/busulfan chemotherapy with autologous stem-cell transplant (ASCT) can defer radiotherapy in newly diagnosed anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA). Forty-one patients were enrolled (85% with 1p/19q codeletion); 21 received HDC-ASCT. After median follow-up of 66 months, the 2-year PFS for transplanted patients was 86%, 5-year PFS was 60%, and no transplanted patient had died (5-year OS 100%). Among all 33 1p/19q-codeleted patients, 5-year PFS was 50% and 5-year OS was 93%. NGS using the MSK-IMPACT 410-gene panel on 19 tumors confirmed the expected oligodendroglioma signature (IDH1, TERT promoter, CIC, FUBP1) in codeleted cases and glioblastoma-like signatures (EGFR amplification/mutation, NF1, MDM2, wild-type IDH1/2) in 1p/19q-intact cases. The full clinical and genomic dataset is available as the odg_msk_2017 cBioPortal study.

Cohort & data

  • Trial: Investigator-initiated multicenter phase II trial sponsored by Memorial Sloan Kettering Cancer Center (NCT00588523), enrolling 41 patients with newly diagnosed anaplastic oligodendroglioma (AO; 36 patients, 88%) or anaplastic oligoastrocytoma (AOA; 5 patients, 12%) between August 2005 and November 2012 PMID:28472509.
  • Eligibility: WHO 2000 diagnosis of AO or AOA (mixed tumors required ≥25% oligodendroglial elements), age ≥18, KPS ≥60. 1p/19q codeletion was assessed but was not an inclusion criterion PMID:28472509.
  • Patient characteristics: 27 men / 14 women; median age 44 years (range 30–66); median KPS 90 (range 70–100); median baseline Mini-Mental State Exam 30 (range 23–30) PMID:28472509.
  • 1p/19q status (FISH, fish-1p19q): 33/39 (85%) codeleted, 6 non-codeleted, 2 unknown PMID:28472509.
  • Treatment regimen: Induction with oral temozolomide 200 mg/m² days 1–5 in 28-day cycles for 6 cycles; responding/SD patients received high-dose chemotherapy with intravenous thiotepa 250 mg/m²/day × 3 (days −8 to −6), then intravenous busulfan 3.2 mg/kg/day × 3 (days −5 to −3), then PBSC reinfusion on day 0 PMID:28472509.
  • Genomic assay: Of 41 enrolled patients, 19 had tissue with adequate DNA for NGS using the MSK-IMPACT assay — a hybridization-capture, Illumina HiSeq 2500 platform with full exon coverage of 410 cancer-related genes (IMPACT410) — 14 with confirmed 1p/19q codeletion and 5 with 1p/19q intact tumors PMID:28472509.
  • Annotation: Sequencing results were matched against the OncoKB database (accessed 6 January 2017) to classify potentially oncogenic and actionable mutations by level of evidence PMID:28472509.
  • Cancer type: Oligodendroglioma, IDH-mutant, 1p/19q-codeleted, Grade 3 (ODG3) — historically called anaplastic oligodendroglioma. Parent code: ODG.
  • Dataset: odg_msk_2017 — clinical and genomic data publicly available at http://cbioportal.org/study?id=odg_msk_2017.
  • Median follow-up of survivors: 65.7 months PMID:28472509.

Key findings

  • Treatment was well tolerated with no toxic deaths. Of 41 enrolled patients, 38 received TMZ (198 cycles total); 29 (70.7%) completed all 6 cycles. Grade 3/4 TMZ toxicities included thrombocytopenia (n=5), lymphopenia (n=3), neutropenia (n=1), hyponatremia (n=1). Among 21 transplanted patients, no toxic deaths were observed. Median time to neutrophil engraftment was 9 days (range 8–12), to platelet engraftment 12 days (range 9–18) PMID:28472509.
  • 2-year PFS in transplanted patients (primary endpoint) was 85.7% (95% CI: 62%–95.2%). 5-year PFS in this group was 60.4% (95% CI: 36%–78%); 5-year OS was 100% — none of the 21 transplanted patients had died at the time of analysis PMID:28472509.
  • Intent-to-treat (N=41) survival: Median PFS 49.5 months; 2-year PFS 66.7% (95% CI: 48.8%–79.5%); median OS not reached; 5-year OS 78.6% (95% CI: 61.6%–88.8%) PMID:28472509.
  • 1p/19q-codeleted population (N=33): Median PFS 62.8 months; 2-year PFS 75.9% (95% CI: 55.9%–87.7%); 5-year PFS 50.3% (95% CI: 30.7%–67%); median OS not reached; 5-year OS 93.4% (95% CI: 76.2%–98.3%). 1p/19q codeletion was a significant predictor of PFS (P = 0.03) and OS (P < 0.001) PMID:28472509.
  • Radiotherapy deferral was substantial. Among 1p/19q-codeleted patients, median time to RT was not reached. At 2 years, 82% of codeleted patients (95% CI: 62%–92%) were alive without RT; at 5 years, 52% (95% CI: 30%–74%) were alive without RT PMID:28472509.
  • Transplant eligibility was tightly tied to 1p/19q codeletion. All 21 transplanted patients lacked intact 1p/19q (20 codeleted, 1 unknown); patients with codeletion preferentially passed induction. 9/35 (25.7%) experienced disease progression during induction TMZ and were referred for RT PMID:28472509.
  • TMZ induction was non-inferior to PCV induction in an exploratory cross-trial comparison. Versus the prior PCV-induction cohort (n=20) with the same HDC/ASCT backbone, the TMZ cohort had longer median OS in all patients (HR 3.38 favoring TMZ, P = 0.005) and in 1p/19q-codeleted patients (HR 5.68, P = 0.018). PFS comparisons trended in the same direction (HR 1.79 all patients, P = 0.086; HR 1.54 codeleted, P = 0.34) PMID:28472509.
  • NGS recapitulated the canonical oligodendroglioma signature. In 19 sequenced tumors, TERT promoter mutation was the most frequent abnormality (18/19), followed by IDH1 (13/19; all R132H), CIC (10/19), NOTCH1 (6/19), NOTCH2 (5/19), and FUBP1 (5/19). None of these alterations were predictive of PFS or OS PMID:28472509.
  • 1p/19q-intact tumors displayed glioblastoma-like signatures. Wild-type IDH1 and IDH2 plus mutations/amplifications in EGFR, NF1, and MDM2 — consistent with de novo glioblastoma — were observed in 1p/19q-intact cases PMID:28472509.
  • NGS exposed a false-positive 1p/19q FISH call. One patient classified as 1p/19q-codeleted by FISH had a glioblastoma-like NGS signature (PTEN loss, CDKN2B and CDKN2AP16INK4A/P14ARF deletion, IDH1/2 wild type) with no NGS evidence of 1p/19q loss; this patient progressed on the first MRI and died at 13 months. The authors recommend NGS as a more reliable 1p/19q screening tool than FISH for trials deferring upfront RT PMID:28472509.
  • Actionable mutations were heterogeneous and individually rare. OncoKB classification of the 19 sequenced tumors identified Level 2B alterations (CDK4 amplification in 2/19; TSC1 total in 1/19), Level 3B alterations (IDH1 R132H in 13/19, IDH2 R172K in 1/19, KRAS Q61H in 1/19, PIK3CA in 2/19), and hotspot mutations of unknown therapeutic implication in EGFR, FBXW7, PIK3R1, and SMARCA4. Other potentially oncogenic mutations spanned APC, ARID1A, ATRX, BCOR, CCND1, CDKN2A, CDKN2B, EGFR amplification, ETV1 amplification, FAT1, GLI1 amplification, KDM6A, MDM2 amplification, MSH2, NF1 (4/19, 21%), PBRM1, PTEN, RASA1, SETD2, and TP53 PMID:28472509.
  • Public data release. Raw clinical and genomic data are available at http://cbioportal.org/study?id=odg_msk_2017 — see odg_msk_2017 — for further meta-analyses PMID:28472509.

Genes & alterations

Clinical implications

  • Chemotherapy-only approach can defer radiotherapy in 1p/19q-codeleted anaplastic oligodendroglioma. With 5-year RT-free survival of 52% in codeleted patients and 5-year OS of 93%, induction TMZ + HDC-ASCT is a viable upfront strategy that may delay RT-related neurotoxicity (cognitive impairment, neuroendocrine disorders, cerebral necrosis) without compromising survival, especially relevant in long-term survivors of this slowly progressive disease PMID:28472509.
  • Single-agent temozolomide is a reasonable substitute for PCV/lomustine/vincristine induction. In an exploratory cross-trial comparison, TMZ-induction patients fared at least as well as the prior PCV cohort with the same myeloablative backbone (HR 3.38 for OS, P = 0.005, all patients) — countering concerns that TMZ is inferior to PCV in this disease PMID:28472509.
  • Chemotherapy alone is not appropriate for 1p/19q-intact tumors. Tumors lacking 1p/19q codeletion progressed early and often had glioblastoma-like NGS signatures; the authors support requiring 1p/19q assessment for trial eligibility in chemotherapy-deferral strategies PMID:28472509.
  • NGS should be considered the screening tool for 1p/19q status in chemotherapy-only trials. A patient classified as 1p/19q-codeleted by FISH but with NGS-detected glioblastoma-like signature died at 13 months, illustrating the clinical cost of false-positive FISH calls when RT is to be deferred PMID:28472509.
  • Aside from IDH1/IDH2, actionable mutations are individually rare and patchy. Each OncoKB-classified actionable alteration (CDK4 amplification, TSC1, PIK3CA, KRAS) was found in only 1–2 of 19 patients, motivating basket-trial designs that pool oligodendroglioma patients with other tumor types sharing the same target PMID:28472509.

Limitations & open questions

  • Continuous follow-up is still required to characterize later endpoints. Although follow-up exceeds 5 years, full assessment of OS in this slow-progressing disease remains incomplete; prospective collection of post-progression imaging and salvage-RT response patterns was not part of the original design PMID:28472509.
  • Neuropsychological outcomes were not formally measured. Although no progression-free patient was reported with neurotoxicity, no formal neuropsychological evaluation was performed, leaving open the central rationale for deferring RT PMID:28472509.
  • No correlative immunology. T-cell repertoire and post-transplant immune-reconstitution studies were not collected, although the dramatically favorable OS relative to PFS suggests an unmeasured immune component may contribute to disease control PMID:28472509.
  • Small sample, voluntary attrition, no randomization. Of 41 enrolled patients, only 21 completed HDC-ASCT (5 refused after eligibility). Cross-trial comparisons with the prior PCV-induction cohort suffer from differing length of follow-up and lack of randomization — TMZ vs PCV non-inferiority within an HDC-ASCT backbone is suggestive, not definitive PMID:28472509.
  • Whether myeloablative HDC + ASCT is necessary versus standard-dose chemotherapy alone is unresolved. The trial does not have an arm of TMZ alone (without transplant); results may not generalize to single-agent TMZ regimens PMID:28472509.
  • NGS analysis was limited to 19/41 patients with adequate tissue/DNA quality, which is too small to test whether non-canonical mutations (e.g. NF1, CDK4, PIK3CA) modify response or prognosis within codeleted tumors. The authors explicitly state that none of TERT/IDH1/CIC/FUBP1/NOTCH1/NOTCH2 was predictive of PFS or OS in this small NGS subset PMID:28472509.
  • The CODEL trial (NCT00887146) previously suggested TMZ-alone was inferior to RT-containing arms (12 vs 24 patients), prompting discontinuation of the TMZ-alone arm; the present authors argue that the CODEL TMZ-alone subset may have been an outlier compared with other prospective chemotherapy-alone studies, but the question remains formally open PMID:28472509.

Citations from this paper used in the wiki

  • “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.” (Abstract).
  • “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.” (Abstract).
  • “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.” (Abstract).
  • “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.” (Abstract).
  • “TERT promoter mutation was the most frequent abnormality, present in 18/19 patients, followed by IDH1 (13/19), CIC (10/19), Notch1 (6/19), Notch2 (5/19), and FUBP1 (5/19). None of these abnormalities were predictive of PFS or OS.” (p. 1385).
  • “1p/19q intact patients … often displayed signatures of de novo glioblastoma-like tumors, including wild-type IDH1 and 2, EGFR amplification and mutation, NF1 mutation, and MDM2 amplification.” (p. 1385).
  • “One patient thought to have 1p/19q codeletion on FISH had a glioblastoma-like signature with PTEN, CDKN2B, CDKN2AP16INK4A, and CDKN2AP14ARF with no evidence of 1p/19q loss or IDH1 or 2 mutation on gene sequencing, suggesting a false-positive 1p/19q codeletion on FISH. That patient progressed on the first MRI and died after 13 months.” (p. 1385).
  • “patients enrolled in the PCV induction cohort achieved a shorter median OS among all patients (median 49.8 mo, hazard ratio [HR]: 3.38, P = 0.005). This difference was also statistically significant among patients with 1p/19q codeletion (N = 11, median OS not reached, HR 5.68, P = 0.018).” (p. 1384).
  • “At 2 years, 82% of patients (95% CI: 0.62%–0.92%) with 1p/19q codeleted tumors were alive without RT and at 5 years 52% were alive without RT (95% CI: 0.3%–0.74%).” (p. 1384).
  • “Raw data for further genomic and meta-analyses are publicly available at http://cbioportal.org/study?id=odg_msk_2017” (Abstract / p. 1389).
  • “the MSK-IMPACT is a hybridization capture-based sequencing assay utilizing an Illumina HiSeq 2500 platform … provides full exon coverage of 410 cancer-related genes” (p. 1382).

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