Diffuse midline glioma H3 K27M-mutant treatment

Diffuse midline glioma H3 K27M-mutant treatment

Stereotactic biopsy is being performed in some centers, and may become routine when therapies specifically targeted to these mutations become available.

Diffuse midline glioma H3 K27M-mutant have no effective treatment, and their location and diffuse nature render them inoperable. Radiation therapy remains the only standard of care for this devastating disease.

Until recently biopsies were considered not informative enough and therefore not recommended.

Systemic administration of chemotherapeutic agents is often hindered by the blood brain barrier (BBB), and even drugs that successfully cross the barrier may suffer from unpredictable distributions. The challenge in treating this deadly disease relies on effective delivery of a therapeutic agent to the bulk tumor as well as infiltrating cells. Therefore, methods that can enhance drug delivery to the brain are of great interest. Convection-enhanced delivery (CED) is a strategy that bypasses the BBB entirely and enhances drug distribution by applying hydraulic pressure to deliver agents directly and evenly into a target region. This technique reliably distributes infusate homogenously through the interstitial space of the target region and achieves high local drug concentrations in the brain. Moreover, recent studies have also shown that continuous delivery of drug over an extended period of time is safe, feasible, and more efficacious than standard single session CED. Therefore, CED represents a promising technique for treating midline tumors with the H3K27M mutation 1).

Based on the molecular heterogeneity observed in this tumor type, personalized treatment is considered to substantially improve therapeutic options. Therefore, clinical evidence for therapy, guided by comprehensive molecular profiling, is urgently required. In this study, we analyzed feasibility and clinical outcomes in a cohort of 12 H3K27M glioma cases treated at two centers. Patients were subjected to personalized treatment either at primary diagnosis or disease progression and received backbone therapy including focal irradiation. Molecular analyses included whole-exome sequencing of tumor and germline DNA, RNA-sequencing, and transcriptomic profiling. Patients were monitored with regular clinical as well as radiological follow-up. In one case, liquid biopsy of cerebrospinal fluid (CSF) was used. Analyses could be completed in 83% (10/12) and subsequent personalized treatment for one or more additional pharmacological therapies could be recommended in 90% (9/10). Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (3/9), MAPK signaling (2/9), immunotherapy (2/9), receptor tyrosine kinase inhibition (2/9), and retinoic receptor agonist (1/9). The overall response rate within the cohort was 78% (7/9) including one complete remission, three partial responses, and three stable diseases. Sustained responses lasting for 28 to 150 weeks were observed for cases with PIK3CA mutations treated with either miltefosine or everolimus and additional treatment with trametinib/dabrafenib in a case with BRAFV600E mutation. Immune checkpoint inhibitor treatment of a case with increased tumor mutational burden (TMB) resulted in complete remission lasting 40 weeks. Median time to progression was 29 weeks. Median overall survival (OS) in the personalized treatment cohort was 16.5 months. Last, we compared OS to a control cohort (n = 9) showing a median OS of 17.5 months. No significant difference between the cohorts could be detected, but long-term survivors (>2 years) were only present in the personalized treatment cohort. Taken together, we present the first evidence of clinical efficacy and an improved patient outcome through a personalized approach at least in selected cases of H3K27M glioma 2).

Although GD2CAR T-cells demonstrated significant anti-tumor activity against Diffuse midline glioma H3 K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. de Billy et al. investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.

Immunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.

GD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual Insulin-like growth factor 1 receptor( IGF1R/IR) antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo and in vivo.

The study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for Diffuse midline glioma H3 K27M-mutant treatment and, potentially, by pHGG 3).

Findings suggest that targeting PLK1 with small-molecule inhibitors, in combination with radiation therapy, will hold a novel strategy in the treatment of Diffuse intrinsic pontine glioma (DIPG) that warrants further investigation 4).


Himes BT, Zhang L, Daniels DJ. Treatment Strategies in Diffuse Midline Gliomas With the H3K27M Mutation: The Role of Convection-Enhanced Delivery in Overcoming Anatomic Challenges. Front Oncol. 2019 Feb 8;9:31. doi: 10.3389/fonc.2019.00031. PMID: 30800634; PMCID: PMC6375835.

Gojo J, Pavelka Z, Zapletalova D, Schmook MT, Mayr L, Madlener S, Kyr M, Vejmelkova K, Smrcka M, Czech T, Dorfer C, Skotakova J, Azizi AA, Chocholous M, Reisinger D, Lastovicka D, Valik D, Haberler C, Peyrl A, Noskova H, Pál K, Jezova M, Veselska R, Kozakova S, Slaby O, Slavc I, Sterba J. Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities. Front Oncol. 2020 Jan 10;9:1436. doi: 10.3389/fonc.2019.01436. PMID: 31998633; PMCID: PMC6965319.

de Billy E, Pellegrino M, Orlando D, Pericoli G, Ferretti R, Businaro P, Ajmone-Cat MA, Rossi S, Petrilli LL, Maestro N, Diomedi-Camassei F, Pezzullo M, De Stefanis C, Bencivenga P, Palma A, Rota R, Del Bufalo F, Massimi L, Weber G, Jones C, Carai A, Caruso S, De Angelis B, Caruana I, Quintarelli C, Mastronuzzi A, Locatelli F, Vinci M. Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant. Neuro Oncol. 2021 Dec 29:noab300. doi: 10.1093/neuonc/noab300. Epub ahead of print. PMID: 34964902.

Amani V, Prince EW, Alimova I, Balakrishnan I, Birks D, Donson AM, Harris P, Levy JM, Handler M, Foreman NK, Venkataraman S, Vibhakar R. Polo-like Kinase 1 as a potential therapeutic target in Diffuse Intrinsic Pontine Glioma. BMC Cancer. 2016 Aug 18;16:647. doi: 10.1186/s12885-016-2690-6. PubMed PMID: 27538997.

Low grade glioma outcome

Low grade glioma outcome

Primary or secondary dissemination develops in 5–10 % 1).

Low-grade gliomas are infiltrative tumors which progressively invade the brain tissue by migrating along the subcortical white matter tracts. Contrary to the indolent characteristics claimed by classical literature, there is a constant growth pattern of these tumors before and after surgery in cases of incomplete resection 2).

The results of a study of Qi et al. indicated that a high Neutrophil to lymphocyte ratio was an independent risk factor for overall survival rates in patients with LGG, which may increase prognostic accuracy and improve patient outcomes 3).

Patients diagnosed with a low-grade glioma are 17 times as likely to die as matched patients in the general population 4).

The age-standardized 10-year relative survival rate was 47% 5).

One study reported that low-grade oligodendroglioma patients have a median survival of 11.6 years; 6), another reported a median survival of 16.7 years 7).

Low grade glioma (LGG) patients have increased life expectancy, so interest is high in the treatments that maximize cognition and quality of life.

Tumor histology, size and IDH-mutation status are important predictors for prolonged overall survival in patients with LGG and may provide a reliable tool for standardizing future treatment strategies 8).

Reports on long-term health related quality of life (HRQL) after surgery for World Health Organization grade II diffuse low-grade gliomas (LGG) are rare.

In two hospital cohorts with different surgical strategies. Biopsy and watchful waiting was favored in one hospital, while early resections guided with three-dimensional (3D) ultrasound was favored in the other. With a population-based approach 153 patients with histologically verified LGG treated from 1998-2009 were included. Patients still alive were contacted for HRQL assessment (n=91) using generic (EQ-5D; EuroQol Group, Rotterdam, The Netherlands) and disease specific (EORTC QLQ-C30 and BN20; EORTC Quality of Life Department, Brussels, Belgium) questionnaires. Results on HRQL were available in 79 patients (87%), 25 from the hospital that favored biopsy and 54 from the hospital that favored early resection. Among living patients there was no difference in EQ-5D index scores (p=0.426). When imputing scores defined as death (zero) in patients dead at follow-up, a clinically relevant difference in EQ-5D score was observed in favor of early resections (p=0.022, mean difference 0.16, 95% confidence interval 0.02-0.29). In EORTC questionnaires pain, depression and concern about disruption in family life were more common with a strategy of initial biopsy only (p=0.043, p=0.032 and p=0.045 respectively).

Although HRQOL remains mostly preserved in the majority of patients with LGG, a subset of patients experience detectable decline on one or more HRQOL scales despite long-term stable disease. For this subgroup, further research is recommended to better aid patients in dealing with the consequences of LGG 9).

In long-term survivors an aggressive surgical approach using intraoperative 3D ultrasound image guidance in LGG does not lower HRQL compared to a more conservative surgical approach. This finding further weakens a possible role for watchful waiting in LGG 10).

Many patients with low-grade glioma experience cognitive dysfunction. However, there is no consensus on how to assess cognitive functioning in these patients 11).

For 22 patients with newly diagnosed LGG who underwent baseline neuropsychological evaluation and magnetic resonance imaging before awake surgery resection with mapping. Twelve of the 22 patients returned for postoperative evaluation approximately 7 months after surgery.

At baseline, 92% of patients/caregivers reported changes in cognition or mood. Neurological examinations and Montreal Cognitive Assessment Scales were largely normal; however, on many tests of memory and language, nearly half of individuals showed deficits. After surgery, 45% had no deficits on neurological examination, whereas 55% had only transient or mild difficulties. Follow-up neuropsychological testing found most performances stable to improved, particularly in language, although some patients showed declines on memory tasks.

Most LGG patients in this series presented with normal neurological examinations and cognitive screening, but showed subjective cognitive and mood concerns and cognitive decline on neuropsychological testing, suggesting the importance of comprehensive evaluation. After awake mapping, language tended to be preserved, but memory demonstrated decline in some patients. These results highlight the importance of establishing a cognitive baseline before surgical resection and further suggest that awake mapping techniques provide reasonable language outcomes in individuals with LGG in eloquent regions 12).

Sexuality after surgery

Sexual dysfunction is common in this population. Therefore, Surbeck et al. suggest that sexual health should consistently be addressed during routine pre- and postoperative examination of patients with DLGG 13).


von Hornstein S, Kortmann RD, Pietsch T et al. Impact of chemo- therapy on disseminated low-grade glioma in children and adolescents: report from the HIT-LGG 1996 trial. Pediatric blood & cancer 2011; 56: 1046–1054

Pallud J, Taillandier L, Capelle L, Fontaine D, Peyre M, Ducray F, et al. Quantitative morphological magnetic resonance imaging follow-up of low-grade glioma: a plea for systematic measurement of growth rates. Neurosurgery. 2012;71:729–739. doi: 10.1227/NEU.0b013e31826213de.

Qi Z, Cai J, Meng X, Cai S, Tang C, Lang L. Prognostic value of preoperative inflammatory markers among different molecular subtypes of lower-grade glioma. J Clin Neurosci. 2021 Nov 18:S0967-5868(21)00513-0. doi: 10.1016/j.jocn.2021.10.006. Epub ahead of print. PMID: 34802893.
4) , 5)

Smoll N, Gautschi OP, Schatlo B, Schaller K, Weber DC (July 6, 2012). “Relative Survival of Patients with Supratentorial Low Grade Gliomas”. Neuro-Oncology.

Ohgaki H, Kleihues P (June 2005). “Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas”

Tanaka K, Sasayama T, Mizukawa K, Takata K, Sulaiman NS, Nishihara M, Kohta M, Sasaki R, Hirose T, Itoh T, Kohmura E. Combined IDH1 mutation and MGMT methylation status on long-term survival of patients with cerebral low-grade glioma. Clin Neurol Neurosurg. 2015 Jul 31;138:37-44. doi: 10.1016/j.clineuro.2015.07.019. [Epub ahead of print] PubMed PMID: 26276726.

Boele FW, Douw L, Reijneveld JC, Robben R, Taphoorn MJ, Aaronson NK, Heimans JJ, Klein M. Health-related quality of life in stable, long-term survivors of low-grade glioma. J Clin Oncol. 2015 Mar 20;33(9):1023-9. doi: 10.1200/JCO.2014.56.9079. Epub 2015 Feb 9. PubMed PMID: 25667287.

Jakola AS, Unsgård G, Myrmel KS, Kloster R, Torp SH, Sagberg LM, Lindal S, Solheim O. Surgical strategies in low-grade gliomas and implications for long-term quality of life. J Clin Neurosci. 2014 Aug;21(8):1304-9. doi: 10.1016/j.jocn.2013.11.027. Epub 2014 May 3. PubMed PMID: 24798909.

van Loon EM, Heijenbrok-Kal MH, van Loon WS, van den Bent MJ, Vincent AJ, de Koning I, Ribbers GM. Assessment methods and prevalence of cognitive dysfunction in patients with low-grade glioma: A systematic review. J Rehabil Med. 2015 Jun 24;47(6):481-8. doi: 10.2340/16501977-1975. PubMed PMID: 25994416.

Racine CA, Li J, Molinaro AM, Butowski N, Berger MS. Neurocognitive Function in Newly Diagnosed Low-grade Glioma Patients Undergoing Surgical Resection With Awake Mapping Techniques. Neurosurgery. 2015 Sep;77(3):371-9. doi: 10.1227/NEU.0000000000000779. PubMed PMID: 25930064.

Surbeck W, Herbet G, Duffau H. Sexuality after surgery for diffuse low-grade glioma. Neuro Oncol. 2015 Apr;17(4):574-9. doi: 10.1093/neuonc/nou326. Epub 2015 Feb 19. PubMed PMID: 25699682.

Diffuse midline glioma H3 K27M-mutant MRI

Diffuse midline glioma H3 K27M-mutant MRI

T1: decreased intensity

T2: heterogeneously increased

T1 C+ (Gd): usually minimal (can enhance post-radiotherapy)

DWI/ADC: usually normal, occasionally mildly restricted

Extensive spread is relatively frequent, both craniocaudally to involve the cerebral hemispheres and spinal cord, as well as leptomeningeal spread 1)

A study included 66 cases (40 in men, 26 in women) of H3 K27M-mutant glioma in adult patients. Tumors were found in the following sites: thalamus (n = 38), brainstem (n = 6), brainstem with cerebellar or thalamic involvement (n = 4), whole-brain (n = 8), corpus callosum (n = 3), hypothalamus (n = 1), hemispheres (n = 2), and spinal cord (n = 4). All pure brainstem lesions were located posteriorly, and all corpus callosal lesions were in the genu. Most spinal tumors were long-segment lesions. Hemispheric lesions mimicked gliomatosis cerebri in presentation, with the addition of traditional midline structure involvement. Most tumors were solid with relatively uniform signals on plain MRI. Of the 61 cases with contrast-enhanced MR images, 36 (59%) showed partial to no enhancement, whereas 25 (41%) showed diffuse or irregular peripheral enhancement. Hemorrhage and edema were rare. Most lesions were solid and showed mild diffusion restriction on diffusion-weighted imaging. Tumor dissemination to the leptomeninges (n = 8) and subependymal layer (n = 3) was observed.

Qiu et al. described the MRI features of diffuse midline glioma with H3 K27M mutation in the largest study done to date in adult patients. Tumors were found in both midline and nonmidline structures, with the thalamus being the most common site. Although adult H3 K27M-mutant gliomas demonstrated highly variable presentations in this cohort of patients, the authors were able to observe shared characteristics within each location 2).

The radiographic features of diffuse midline gliomas with histone H3 K27M mutation were highly variable, ranging from expansile masses without enhancement or necrosis with large areas of surrounding infiltrative growth to peripherally enhancing masses with central necrosis with the significant mass effect but little surrounding T2/FLAIR hyperintensity. When we compared diffuse midline gliomas on the basis of the presence or absence of histone H3 K27M mutation, there was no significant correlation between enhancement or border characteristics, infiltrative appearance, or presence of edema 3)

Zhuo et al. from the Beijing Tiantan Hospital aimed to predict H3K27M mutation status by Amide proton transfer imaging (APTw) and radiomic features.

Methods: Eighty-one BSG patients with APTw imaging at 3T MR and known H3K27M status were retrospectively studied. APTw values (mean, median, and max) and radiomic features within manually delineated 3D tumor masks were extracted. Comparison of APTw measures between H3K27M-mutant and wildtype groups was conducted by two-sample Student’s T/Mann-Whitney U test and receiver operating characteristic curve (ROC) analysis. H3K27M-mutant prediction using APTw-derived radiomics was conducted using a machine learning algorithm (support vector machine) in randomly selected train (n = 64) and test (n = 17) sets. Sensitivity analysis with additional random splits of train and test sets, 2D tumor masks, and other classifiers were conducted. Finally, a prospective cohort including 29 BSG patients was acquired for validation of the radiomics algorithm.

Results: BSG patients with H3K27M-mutant were younger and had higher max APTw values than those with wildtype. APTw-derived radiomic measures reflecting tumor heterogeneity could predict H3K27M mutation status with an accuracy of 0.88, the sensitivity of 0.92, and specificity of 0.80 in the test set. Sensitivity analysis confirmed the predictive ability (accuracy range: 0.71-0.94). In the independent prospective validation cohort, the algorithm reached an accuracy of 0.86, the sensitivity of 0.88, and specificity of 0.85 for predicting H3K27M-mutation status.

Conclusion: BSG patients with H3K27M-mutant had higher max APTw values than those with wildtype. APTw-derived radiomics could accurately predict an H3K27M-mutant status in BSG patients 4).

Piccardo et al., from Genoa, retrospectively analyzed 22 pediatric patients with DMG histologically proved and molecularly classified as H3K27M-mutant (12 subjects) and wild-type (10 subjects) who underwent DWIProton magnetic resonance spectroscopic imaging, and ASL performed within 2 weeks of 18F-FDOPA PET. DWI-derived relative minimum apparent diffusion coefficient (rADC min), 1H-MRS data choline/N-acetylaspartate (Cho/NAA), choline/creatine (Cho/Cr), and presence of lactate and relative ASL-derived cerebral blood flow max (rCBF max) were compared with 18F-DOPA uptake Tumor/Normal tissue (T/N) and Tumor/Striatum (T/S) ratios, and correlated with histological and molecular features of DMG. Statistics included Pearson’s chi-squared test and Mann-Whitney U tests, Spearman’s rank correlation and receiver operating characteristic (ROC) analysis.

The highest degrees of correlation among different techniques were found between T/S, rADC min and Cho/NAA ratio (p < 0.01), and between rCBF max and rADC min (p < 0.01). Significant differences between histologically classified low- and high-grade DMG, independently of H3K27M-mutation, were found among all imaging techniques (p ≤ 0.02). Significant differences in terms of rCBF max, rADC min, Cho/NAA and 18F-DOPA uptake were also found between molecularly classified mutant and wild-type DMG (p ≤ 0.02), even though wild-type DMG included low-grade astrocytomas, not present among mutant DMG. When comparing only histologically defined high-grade mutant and wild-type DMG, only the 18F-DOPA PET data T/S demonstrated statistically significant differences independently of histology (p < 0.003). ROC analysis demonstrated that T/S ratio was the best parameter for differentiating mutant from wild-type DMG (AUC 0.94, p < 0.001).

Advanced MRI and 18F-DOPA PET characteristics of DMG depend on histological features; however, 18F-DOPA PET-T/S was the only parameter able to discriminate H3K27M-mutant from wild-type DMG independently of histology 5).


Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007 Aug;114(2):97-109. doi: 10.1007/s00401-007-0243-4. Epub 2007 Jul 6. Erratum in: Acta Neuropathol. 2007 Nov;114(5):547. PMID: 17618441; PMCID: PMC1929165.

Qiu T, Chanchotisatien A, Qin Z, Wu J, Du Z, Zhang X, Gong F, Yao Z, Chu S. Imaging characteristics of adult H3 K27M-mutant gliomas. J Neurosurg. 2019 Nov 15:1-9. doi: 10.3171/2019.9.JNS191920. Epub ahead of print. PMID: 31731269.

Aboian MS, Solomon DA, Felton E, Mabray MC, Villanueva-Meyer JE, Mueller S, Cha S. Imaging Characteristics of Pediatric Diffuse Midline Gliomas with Histone H3 K27M Mutation. AJNR Am J Neuroradiol. 2017 Apr;38(4):795-800. doi: 10.3174/ajnr.A5076. Epub 2017 Feb 9. PMID: 28183840; PMCID: PMC5394943.

Zhuo Z, Qu L, Zhang P, Duan Y, Cheng D, Xu X, Sun T, Ding J, Xie C, Liu X, Haller S, Barkhof F, Zhang L, Liu Y. Prediction of H3K27M-mutant brainstem glioma by amide proton transfer-weighted imaging and its derived radiomics. Eur J Nucl Med Mol Imaging. 2021 Jun 16. doi: 10.1007/s00259-021-05455-4. Epub ahead of print. PMID: 34131804.

Piccardo A, Tortora D, Mascelli S, Severino M, Piatelli G, Consales A, Pescetto M, Biassoni V, Schiavello E, Massollo M, Verrico A, Milanaccio C, Garrè ML, Rossi A, Morana G. Advanced MR imaging and (18)F-DOPA PET characteristics of H3K27M-mutant and wild-type pediatric diffuse midline gliomas. Eur J Nucl Med Mol Imaging. 2019 Apr 27. doi: 10.1007/s00259-019-04333-4. [Epub ahead of print] PubMed PMID: 31030232.
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