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Intratumoral and intracranial hemorrhage has emerged as a clinically relevant safety signal, but drug-specific incidence estimates, phenotypic definitions, and contributing mechanisms remain incompletely characterized. We systematically reviewed the evidence and synthesized contributing mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed a systematic review of PubMed\/MEDLINE and Embase from database inception through May 2026, supplemented by FDA prescribing information, to identify studies reporting intratumoral or intracranial hemorrhage with MAPK-pathway targeted agents across tumor types. Results were synthesized narratively given heterogeneity in reporting definitions and study designs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CNS hemorrhage signals were identified across agents. Dabrafenib-based regimens in melanoma brain metastases produced ICH rates of 6% (BREAK-MB monotherapy) and a fatal hemorrhage in 0.8% (COMBI-MB combination). In the phase 2 FIREFLY-1 trial of tovorafenib in BRAF-altered pLGG (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009137), any-site hemorrhage of any grade occurred in 42% of patients with grade 3\u20134 hemorrhage in 7 patients (5%) and, separately, one fatal grade 5 intratumoral hemorrhage; in the overlapping pooled FDA-label safety population (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u2009140), intratumoral hemorrhage specifically was reported in 9%. Combining BRAF inhibitors with stereotactic radiosurgery was associated with 3-fold higher odds of ICH versus radiosurgery alone (OR 3.16; 95% CI 1.43\u20136.96).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>MAPK-pathway inhibitors are associated with a consistent but heterogeneous CNS hemorrhage signal. Reported incidence varies by agent, population, and hemorrhage ascertainment method (active imaging-based surveillance versus clinical reporting), from &lt;\u20091% symptomatic ICH with dabrafenib in adult melanoma to 9% intratumoral hemorrhage in the pooled pediatric tovorafenib safety population. Standardized definitions, CNS-specific CTCAE capture, and prospective imaging surveillance are needed to define true incidence and risk as MAPK-directed therapy expands in neuro-oncology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Registration<\/jats:title>\n                    <jats:p>This systematic review was not prospectively registered in PROSPERO.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11060-026-05714-0","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T10:23:28Z","timestamp":1784111008000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intratumoral and intracranial hemorrhage associated with MAPK-pathway targeted therapy: a systematic review and mechanistic synthesis"],"prefix":"10.1007","volume":"178","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4738-6356","authenticated-orcid":false,"given":"Sudarshawn","family":"Damodharan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra","family":"Calderon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed S.","family":"Abdelbaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"5714_CR1","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1016\/j.ccell.2020.03.011","volume":"37","author":"S Ryall","year":"2020","unstructured":"Ryall S, Zapotocky M, Fukuoka K et al (2020) Integrated molecular and clinical analysis of 1,000 pediatric low-grade gliomas. 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