Late-onset radiation-induced brain necrosis following allogeneic transplantation for CNS-involved acute myeloid leukemia after whole brain irradiation: two case reports

1. INTRODUCTION Central nervous system (CNS) involvement occurs in about 3% of acute myeloid leukemia (AML) cases and is associated with poor prognosis.1 Allogeneic hematopoietic cell transplantation (HCT) remains one of the few strategies to reduce CNS relapse and improve survival.2 Achieving CNS remission before transplantation is crucial, as it improves overall survival,3 and CNS irradiation may be added to intrathecal chemotherapy (ITC) to enhance control.4 However, post-HCT neurotoxicity encompasses leukoencephalopathy, CNS infections, and medication-induced effects, necessitating careful differential diagnosis, particularly in patients who received CNS-directed therapies.5 Radiation-induced brain necrosis (RBN) is a particular serious and often irreversible complication of cranial radiotherapy. RBN occurs in over 5% of patients receiving focal irradiation for brain tumors when a biologically effective dose exceeding 120 Gy is delivered, typically with standard fractionation of 2 to 2.5 Gy per fraction.6 Early detection and timely management are essential, yet differentiating RBN from tumor recurrence or other post-treatment changes remains challenging. Recently, imaging modalities such as positron emission tomography (PET) using L-[methyl-11C] methionine (11C-methionine PET) and magnetic resonance spectroscopy (MRS) have emerged as valuable diagnostic tools, often used alongside brain biopsy.7,8 To date, no biopsy-confirmed RBN cases following allogeneic HCT have been reported. A PubMed search in June 2025 using the terms “radiation necrosis,” “allogeneic transplantation,” and “central nervous system” identified no such cases. Here, we present 2 rare cases of late-onset CNS lesions after allogeneic HCT ultimately diagnosed as RBN, highlighting the diagnostic complexity of this underrecognized entity. 2. CASE PRESENTATION 2.1. Case 1 A 35-year-old man was diagnosed with AML with a t (9;11) translocation (Fig. 1A). After induction and consolidation therapy, he achieved complete remission (CR). In February, 5 years after AML diagnosis, cerebrospinal fluid (CSF) analysis confirmed CNS relapse. He received whole brain irradiation (WBI) (40 Gy in 20 fractions) and 4 doses of ITC (methotrexate 15 mg, cytarabine 40 mg, and prednisolone 20 mg). In July, he underwent allogeneic peripheral blood stem cell transplantation from an human leukocyte antigen (HLA)-matched sibling. Conditioning included fludarabine (180 mg/m²), busulfan (12.8 mg/kg), and melphalan (80 mg/m²), with cyclosporine and methotrexate for graft-versus-host disease prophylaxis. Neutrophil engraftment was achieved by day 12, and CR was maintained. Two additional intrathecal doses were administered as prophylaxis against CNS relapse. Two years after WBI, magnetic resonance imaging (MRI) revealed a new cerebellar lesion that resolved spontaneously. Three years after WBI, a corpus callosum mass and cortical white matter lesion appeared. Both CNS relapse and RBN were suspected, although CSF findings remained unremarkable. An 11C-methionine PET demonstrated ring-enhancing methionine uptake, with a maximum standardized uptake values (SUVmax) of 1.63 and a lesion-to-normal (L/N) mean of 1.07, suggestive of RBN rather than CNS relapse. As the patient was asymptomatic, he was managed under observation. Three years after WBI, the lesion enlarged, and right upper extremity weakness developed. MRS revealed elevated lipid/lactate peaks in the lesion, but elevated the choline-to-creatine (Cho/Cr) ratio (ranging from 1.48 to 2.95), making it difficult to distinguish between tumor recurrence and RBN (Fig. 1C and D). Symptoms improved with dexamethasone 4 mg/d, which was tapered. Five years after WBI, MRI showed a new lesion near the right lateral ventricle. As MRS could not exclude relapse, stereotactic biopsy was performed. Histopathological examination revealed coagulative necrosis, scattered foamy macrophages, and several thick-walled, hyalinized blood vessels, with no significant inflammatory cell infiltration, findings consistent with RBN (Fig. 2A and B). Prednisolone 20 mg/d was started, but tapering caused recurrent dizziness requiring adjustments. He has remained on long-term corticosteroid therapy for 8 years without adverse effects and is relapse-free 9 years posttransplant. Cognitive function has remained intact since transplantation, and the patient is fully independent in both daily life and employment.Figure 1.: Clinical courses. (A) Case 1. (B) Case 2. (C and D) MR imaging and MRS (case 1). (C) shows findings in the normal-appearing region, while (D) depicts the lesion. Four voxels outlined in yellow boxes were individually analyzed, and their results are shown below the MR images in a corresponding positional layout (for example, the upper left yellow voxel corresponds to the upper left MRS spectrum below). In (D), MRS spectra from these voxels show elevated lipid/lactate peaks and increased Cho/Cr ratios (range: 1.48–2.95). AML = acute myeloid leukemia, CBT = cord blood transplantation, Cho/Cr = choline-to-creatine ratio, CNS = central nervous system, CSF = cerebrospinal fluid, Dex = dexamethasone, EBV = Epstein-Barr virus, MR = magnetic resonance, MRS = MR spectroscopy, PSL = prednisolone, Rit = rituximab, R-PBSCT = related peripheral blood stem cell transplantation, WBI = whole brain irradiationFigure 2.: Histology of the brain tissues. Histology of the brain tissues obtained through surgical biopsy in case 1 (A and B) and case 2 (C–F) reveals extensive necrotic areas (denoted by *, A–D) along with clustered foamy macrophages nearby (E) and thickened blood vessels exhibiting prominent hyalinization (F). Intact white matter is denoted by “W” (hematoxylin and eosin; A, C: bar = 1 mm, B, D–F: bar = 100 µm).2.2. Case 2 A 28-year-old man was diagnosed with AML-M2 (FAB classification) and underwent cord blood transplantation (CBT; Fig. 1B). Two years after CBT, brain MRI revealed a left frontal mass, and CSF confirmed CNS relapse. He received 6 intrathecal doses with the same regimen as case 1, and WBI at 24 Gy in 15 fractions. Although MRI showed lesion shrinkage, pretransplant CSF still revealed blasts. He subsequently underwent a second CBT, with neutrophil engraftment on day 31 and CSF blast clearance. WBI was reinitiated at 16 Gy in 8 fractions, with a 20 Gy boost to the frontal mass on day 63, and 2 additional intrathecal doses were administered. The patient remained in CR. Two years after WBI, MRI revealed a new corpus callosum lesion, and a craniotomy was performed. Histopathological analysis revealed infarct-like necrotic areas with clusters of foamy macrophages and markedly hyalinized, thick-walled blood vessels (Fig. 2C-F). There was no evidence of blast infiltration, findings strongly suggestive of RBN. As the patient was asymptomatic, he was placed under observation. Four months after biopsy, he developed memory impairment, but MRI was unchanged. CSF revealed Epstein-Barr virus DNA (2.54 × 10² copies/mL); post-transplant lymphoproliferative disorder was suspected, and rituximab was administered. Symptoms persisted, and MRI showed enlargement of the left frontal mass, raising concern for CNS relapse. A second craniotomy again confirmed RBN. Dexamethasone 40 mg daily was initiated and tapered. Three years after WBI, he developed methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, and the intracranial lesion was suspected to be a brain abscess. Nevertheless, neither CNS relapse nor RBN could be definitively ruled out. An 11C-methionine PET scan demonstrated ring-enhancing methionine uptake in the left frontal lobe, with a SUVmax of 2.58 and an L/N mean of 1.91. Tumor recurrence could not be excluded; resection was performed. Histology again confirmed RBN. The patient stabilized during corticosteroid tapering without adverse effects and remains relapse-free 10 years posttransplant. While motor and sensory functions remain intact, the patient developed cognitive decline following memory impairment, requiring partial assistance in daily activities and ongoing vocational rehabilitation. 3. DISCUSSION We report 2 biopsy-confirmed cases of late-onset RBN after allogeneic HCT, further supported by 11C-methionine PET and MRS. To our knowledge, this is the first such report, underscoring the importance of considering RBN in the differential diagnosis of posttransplant CNS lesions. Both patients underwent allogeneic HCT with WBI for CNS involvement in relapsed/refractory AML and subsequently achieved long-term relapse-free survival. Although WBI or craniospinal irradiation combined with HCT has been reported as a favorable prognostic factor in CNS leukemia,9 the potential for late adverse effects like RBN remains insufficiently characterized. Combined CNS-directed therapies heighten neurotoxicity risk; methotrexate and cytarabine may exacerbate radiation-induced injury by impairing glial repair and microvascular integrity, predisposing patients to RBN.6,10 Moreover, myeloablative conditioning and prolonged immunosuppression can hinder neurovascular repair and blood-brain barrier recovery, synergistically increasing susceptibility to radiation-related CNS injury.11,12 Consequently, in HCT recipients with prior CNS-directed therapy, the risk of post-transplant CNS complications is particularly high. In both our cases, the earliest lesions appeared in the corpus callosum. This area may be especially susceptible due to the vulnerability of central white matter tracts to delayed demyelination and necrosis, supported by evidence that radiation damage preferentially involves densely myelinated regions.13 Differentiating CNS relapse from treatment-related lesions is challenging. RBN is a rare late complication of cranial radiotherapy, typically arising months to years post-treatment.14 Conventional imaging cannot reliably distinguish it from recurrence, but 11C-methionine PET and MRS are helpful. On 11C-methionine PET, an L/N mean >2.69 suggests recurrence, while <1.41 favors RBN.7,15,16 Accordingly, RBN was strongly suspected in case 1, whereas recurrence could not be excluded in case 2. MRS may help differentiate, with a Cho/Cr ratio >1.11 suggesting glioma recurrence.17,18 However, elevated Cho/Cr ratios can also be seen in RBN,19 and in case 1, a lipid/lactate peak—commonly associated with necrosis and ischemia—supported RBN.20 Thus, careful interpretation is required, and histopathology ultimately confirmed the diagnosis. Brain biopsy remains the diagnostic gold standard. In both cases, histopathology demonstrated coagulative or infarct-like necrosis, clusters of foamy macrophages, and hyalinized thick-walled vessels, without tumor or significant inflammation—findings consistent with RBN.21 Because sampling error may miss residual tumor components, a definitive diagnosis should integrate histopathology with clinical course and advanced imaging to minimize misclassification. RBN prognosis depends on clinical context and necrosis extent. In our cases, both patients achieved long-term survival and functional independence with corticosteroid therapy, likely because the lesions were localized to noneloquent regions and spared the brainstem.22 Steroid responsiveness allowed symptom control and prevented further deterioration, contrasting with the typically poor prognosis of CNS relapse in AML.23 Corticosteroid therapy was required for 6 years in case 1 and 7 in case 2. In case 2, MRSA bacteremia developed but was controlled with antibiotics, and no additional severe infections occurred during follow-up. Alternatives such as bevacizumab and hyperbaric oxygen were considered in steroid-refractory cases; however, corticosteroids remained effective, with dosing (typically dexamethasone 4–8 mg/d) and tapering individualized to symptoms and imagings.24 In conclusion, we report 2 cases of late-onset RBN following WBI, ITC, and allogeneic HCT for CNS-involved AML. This rare complication presents significant diagnostic challenges, particularly in distinguishing it from relapse. A comprehensive approach, incorporating advanced imaging and histology, is essential for timely diagnosis and optimal management. ETHICAL APPROVAL This case study was conducted in accordance with the Declaration of Helsinki. AUTHOR CONTRIBUTIONS J.Y. collected the data. J.Y. and S.T. wrote the manuscript. S.I. and T.F., as pathologists, diagnosed radiation-induced brain necrosis and provided the pathological images. All authors approved the final manuscript.