BIOM-28. SERIAL PLASMA AND CSF CELL-FREE TUMOR DNA (cf-tDNA) TRACKING IN DIFFUSE MIDLINE GLIOMA PATIENTS UNDERGOING TREATMENT WITH ONC201

Abstract Diffuse midline glioma (DMG) with H3K27M mutation is a lethal childhood brain cancer, with limited means of monitoring beyond serial MRI scans. We conducted a multi-site Phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients on Arm D of the trial (n=24) underwent serial lumbar puncture (baseline, 2 and 6-months) for cell-free tumor DNA (cf-tDNA) analysis at time of MRI. Additionally, patients on all arms of the trial at the University of Michigan underwent serial plasma collection. We collected a total of 96 plasma-samples and 53 CSF-samples from 29 patients. We performed ddPCR analysis of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal tumor area on MRI). For our H3F3A-mutated (K27M) patients, cf-tDNA was positive in 53/62 plasma samples (sensitivity 85.4%) and 28/29 CSF samples (sensitivity 96.5%) and overall specificity of 100%. There was no direct correlation between percent-change in tumor-area and plasma (p=0.47) or CSF VAF (p=0.89), implying that VAF provided information supplemental to radiographic assessments. “Spikes” in plasma cf-tDNA VAF (increase of ≥25%) co-occurred with progression in 2/9 (22%) cases and preceded progression in 5/9 cases (55%) by an average of 1.22 months. In CSF, spikes preceded progression in 4/6 cases (66%) by an average of 1.8 months. Two patients had increases in tumor-area with no increase in plasma VAF; both were later confirmed as pseudo-progressors, suggesting additional potential utility of cf-tDNA VAF monitoring. A 14yo male with spinal cord glioma received concurrent bevacizumab with ONC201, which resulted in a decrease in tumor area but continued increase in plasma VAF, predicting radiologic progression at the next time. In summary, we present data which suggests monitoring serial CSF/plasma H3K27M tDNA is a promising clinical tool. Changes in cf-tDNAVAF over time appear to correlate with response, predict progression, and differentiate pseudo-progression.

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Serial plasma and CSF cell-free tumor DNA (cf-tDNA) tracking in diffuse midline glioma patients undergoing treatment with ONC201.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2012 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2012-2012

Author(s):

Evan Cantor ◽

Kyle Wierzbicki ◽

Rohinton Tarapore ◽

Chase Thomas ◽

Rodrigo Cartaxo ◽

...

Keyword(s):

Tumor Size ◽

Clinical Decision Making ◽

Phase 1 ◽

Complete Response ◽

Clinical Decision ◽

Experimental Therapy ◽

Plasma Samples ◽

Mri Scans ◽

Tumor Dna ◽

Diffuse Midline Glioma

2012 Background: Diffuse midline glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis. There are few available means of monitoring the disease beyond serial MRI scans, making clinical decision making slow, difficult, and often reactive. Methods: We conducted a multi-site phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n=24) underwent serial lumbar puncture (baseline, 2 and 6 months) for cell-free tumor DNA (cf-tDNA) analysis at time of MRI. Additionally, patients on all arms of the trial at the University of Michigan underwent serial plasma collection. CSF collection was feasible in this cohort, with no procedural complications. We collected a total of 96 plasma samples and 53 CSF samples from 29 patients, including those with H3F3A (H3.3) (n=13), HIST13HB (H3.1) (n= 4), and unknown H3 status/not biopsied (n=12) [range of 0-8 CSF samples and 0-10 plasma samples]. We performed digital droplet polymerase chain reaction (ddPCR) analysis and/or amplicon-based electronic sequencing (Oxford Nanopore) of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI). Results: Preliminary analysis of samples (n=58) demonstrates a correlation between changes in tumor size and H3K27M cf-tDNA VAF, when removing samples with concurrent bevacizumab. Analysis of remaining CSF and plasma samples is ongoing, including analysis of novel biomarkers of response. In multiple cases, early reduction in CSF cf-tDNA predicts long-term clinical response (>1 year) to ONC201 and does not increase in cases of later-defined pseudo-progression (radiation necrosis). For example, a now 9-year old patient with thalamic H3K27M-mutant DMG underwent treatment with ONC201 after initial radiation and developed an increase in tumor size at 4 months post-radiation (124% baseline) of unclear etiology at the time. Meanwhile, her ddPCR declined from baseline 6.76% VAF to <1%, which has persisted, with now near complete response (85% tumor reduction) at 30 months on treatment from diagnosis. Conclusions: In summary, we present the feasibility and utility of serial CSF/plasma monitoring of a promising experimental therapy for DMG.

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EPCT-03. SERIAL PLASMA AND CSF CELL-FREE TUMOR DNA (CF-TDNA) TRACKING IN DIFFUSE MIDLINE GLIOMA PATIENTS UNDERGOING TREATMENT WITH ONC201

Neuro-Oncology ◽

10.1093/neuonc/noab090.189 ◽

2021 ◽

Vol 23 (Supplement_1) ◽

pp. i46-i47

Author(s):

Evan Cantor ◽

Kyle Wierzbicki ◽

Rohinton S Tarapore ◽

Chase Thomas ◽

Rodrigo Cartaxo ◽

...

Keyword(s):

Tumor Size ◽

Phase 1 ◽

Complete Response ◽

Experimental Therapy ◽

Plasma Samples ◽

Oxford Nanopore ◽

Procedural Complications ◽

Unclear Etiology ◽

Tumor Dna ◽

Diffuse Midline Glioma

Abstract Diffuse midline glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis. We conducted a multi-site Phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n=24) underwent serial lumbar puncture (baseline, 2, 6 months) for cell-free tumor DNA (cf-tDNA) analysis at time of MRI. Additionally, patients on all arms of the trial at the University of Michigan underwent serial plasma collection. CSF collection was feasible in this cohort, with no procedural complications. We collected 96 plasma samples and 53 CSF samples from 29 patients, including those with H3F3A (H3.3) (n=13), HIST13HB (H3.1) (n= 4), and unknown H3 status/not biopsied (n=12) [range of 0–8 CSF samples and 0–10 plasma samples]. We performed digital droplet polymerase chain reaction (ddPCR) analysis and/or amplicon-based electronic sequencing (Oxford Nanopore) of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI). Preliminary analysis of samples demonstrates a correlation between changes in tumor size and H3K27M cf-tDNA VAF, when removing samples with concurrent bevacizumab. In multiple cases, early reduction in CSF cf-tDNA predicts long-term clinical response (>1 year) to ONC201, and does not increase in cases of later-defined pseudo-progression (radiation necrosis). For example, a now 9-year old patient with thalamic H3K27M-mutant DMG underwent treatment with ONC201 after initial radiation and developed increase in tumor size at 4 months post-radiation (124% baseline) of unclear etiology at the time. Meanwhile, her ddPCR declined from baseline 6.76% VAF to <1%, which has persisted, with now near complete response (15% tumor reduction) at 30 months on treatment from diagnosis. In summary, we present the feasibility and utility of serial CSF/plasma monitoring of a promising experimental therapy for DMG.

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Novae in the Magellanic Clouds

International Astronomical Union Colloquium ◽

10.1017/s0252921100073334 ◽

1979 ◽

Vol 46 ◽

pp. 96-101

Author(s):

J.A. Graham

Keyword(s):

Large Magellanic Cloud ◽

Magellanic Cloud ◽

Magellanic Clouds ◽

University Of Michigan ◽

The Past ◽

Spectroscopic Information ◽

Objective Prism ◽

The University ◽

Small Cloud ◽

Low Dispersion

During the past several years, a systematic search for novae in the Magellanic Clouds has been carried out at Cerro Tololo Inter-American Observatory. The Curtis Schmidt telescope, on loan to CTIO from the University of Michigan is used to obtain plates every two weeks during the observing season. An objective prism is used on the telescope. This provides additional low-dispersion spectroscopic information when a nova is discovered. The plates cover an area of 5°x5°. One plate is sufficient to cover the Small Magellanic Cloud and four are taken of the Large Magellanic Cloud with an overlap so that the central bar is included on each plate. The methods used in the search have been described by Graham and Araya (1971). In the CTIO survey, 8 novae have been discovered in the Large Cloud but none in the Small Cloud. The survey was not carried out in 1974 or 1976. During 1974, one nova was discovered in the Small Cloud by MacConnell and Sanduleak (1974).

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