H3K27M-mutated diffuse midline glioma (H3K27M-DMG) may arise in the pons, thalamus and spinal cord generally having a dismal prognosis. Notably, H3K27M-DMG are driven by oligodendrocyte precursor-like cells which are partly sustained by PDGFRA signaling. Co-mutations including TP53, ACVR1, PDGFRA, KIT and PI3K pathway alterations are present in a subset of cases, and molecular profiling may allow detection of additional targetable alterations. However, small-molecule inhibitors often have limited efficacy associated with low blood-brain-barrier (BBB) penetration. Here, we report on a patient with spinal, leptomeningeal disseminated H3K27M-DMG treated with avapritinib, an orally administered, BBB-penetrant and highly selective KIT and PDGFR inhibitor, provided through a compassionate-use program. Initial therapy consisted of subtotal resection, focal radiotherapy and temozolomide (TMZ) resulting in disease stabilization. Ten months after diagnosis, leptomeningeal metastases were detected, biopsied and treated with local irradiation and TMZ. The patient subsequently received systemic and intrathecal chemotherapy augmented with dasatinib. Molecular analyses of the biopsy revealed the H3F3A and TP53 mutations present in the primary tumor, as well as de novo PDGFRA and KIT amplifications with gene copy numbers of 25 and 21, respectively. Upon further disease progression, therapy with avapritinib was initiated. Assessment of treatment response according to RANO criteria after four months revealed stable disease of the target lesion in the cerebellum and partial response of all non-target lesions. Avapritinib was generally well tolerated with lower limb edema (Grade 2), small intratumoral bleeding (Grade 1) and unrelated hydrocephalus (Grade 3) as reported adverse events. As precaution, treatment was interrupted and re-initiated after one week as the bleeding was stable. A ventriculoperitoneal shunt was implanted resolving the hydrocephalus. Pharmacokinetic analyses revealed up to 65% avapritinib plasma exposure and clinically relevant levels in cerebrospinal fluid. In summary, we report on first effective therapy of treatment-resistant H3K27M-DMG with avapritinib as clinical proof of concept.
H3K27M-mutated diffuse midline glioma (H3K27M DMG) are an almost universally fatal disease with a median survival of less than 6 months post progression and no effective therapy. PDGFRA-signaling has shown to promote and sustain a subset of oligodendrocyte precursor-like tumor cells that are responsible for tumor propagating potential and high proliferation rates. However, first attempts to target PDGFRA in adult glioblastoma with dasatinib/imatinib or pediatric refractory brain tumors with sunitinib were not successful. We report on the first experience in two patients receiving avapritinib, a highly potent, selective, brain penetrant PDGFRA/KIT inhibitor under a compassionate use program. Our first patient with spinal H3K27M DMG developed supratentorial metastases ten months after initial diagnosis. Molecular profiling revealed de novo PDGFRA and KIT amplifications and treatment with dasatinib was initiated. Due to disease progression and novel metastases, therapy was switched to avapritinib showing near complete resolution of the previously unirradiated frontal lesion with additional disease stabilization of other metastatic sites. Following re-resection and irradiation of progressing cerebellar lesions, the patient remains clinically stable on avapritinib therapy over 12 months. The second patient with diffuse intrinsic pontine glioma showed disease progression nine months after diagnosis and was treated with focal re-irradiation (30Gy). As the tumor harbored a PDGFRA R841del alteration, avapritinib was initiated seven weeks after radiation upon further tumor progression resulting in partial response. Pharmacokinetic sampling of cerebrospinal fluid (CSF) detected an increasing CSF/plasma ratio over time and up to 4 µM avapritinib in tumor tissue. Avapritinib CSF levels in both patients were distinctly higher than dasatinib levels. Avapritinib was generally well tolerated besides lower limb edema, elevated LDH and liver enzymes. Hence, effective CNS penetration of avapritinib at pharmacologically relevant brain tumor concentrations resulted in clinical response in two patients with rapidly progressive H3K27M DMG.
PURPOSE: Advances in treatment have increased survival rates and quality of life of pediatric CNS tumor patients leading to a growing number of long-term survivors. However, there is sufficient clinical and scientific evidence for the need of a highly specialized lifelong follow-up care due to multidimensional late effects. Furthermore, adolescence and young adulthood are challenging age periods when patients frequently get lost to follow-up potentially having severe impact on health and well-being. Since 2020, we have established a structured transfer of long-term survivors older than 18 years to a newly founded highly specialized adult care follow-up setting for childhood cancer survivors (IONA). The aim of this study was to evaluate the current transition process. RESEARCH DESIGN: The standard of care transition process at the neuro-oncology unit of the MUV includes a joint appointment with the patient, a pediatric neuro-oncologist, psychologist and/or social worker and the team of the adult care facility (physician, psychologist). Different elements are used to end care safely in the pediatric structure and building trust in the upcoming out-patient-department at the same time. The transition process was evaluated statistically and analyzed qualitatively with regard to the factors that define a safe transition. RESULTS: After two years (01/2020-12/2021) 114 patients had a joint transition appointment, two patients contacted IONA directly. Shortly after the joint appointment all patients had a scheduled follow-up meeting at IONA. 102 patients (87.9%) showed up, seven patients (6%) already had a planned appointment, two patients (1.7%) were in contact with IONA but had no possibility to show up in person. Only five patients (4.3%) did not attend the appointment and were lost to follow-up. CONCLUSION: A structured interdisciplinary transition concept is a successful option to establish controlled and patient-safe transition from pediatric to adult care setting.
ZusammenfassungNeurofibromatose Typ 1 (NF1) ist ein autosomal dominantes Tumorprädispositionssyndrom, dessen Verlauf nicht vorhersagbar ist und das in Abhängigkeit der Schwere der Symptome vom Kindesalter an eine lebenslange Betreuung durch SpezialistInnen erfordert. Neben harmlosen Hautmanifestationen (u. a. Café-au-lait-Flecken) kann es auch zu Tumoren (Neurofibrome, Optikusgliome, plexiforme Neurofibrome), zu Störungen der Knochenentwicklung, kardiovaskulären sowie endokrinologischen Problemen, aber auch zu Lern- und Entwicklungsstörungen kommen. Aufgrund des heterogenen Verlaufs und der Vielfältigkeit möglicher Symptome kann das Diagnose- und Therapiemanagement herausfordernd sein, wobei ein 2017 gegründetes NF1-Expertisezentrum (in Kooperation zwischen der Patientenorganisation NF-Kinder und der Univ.-Klinik für Kinder- und Jugendheilkunde an der Medizinischen Universität Wien, AKH Wien) Hilfestellung für Betroffene aller Altersstufen im medizinischen wie auch psychosozialen Bereich anbietet.
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