Daud, Adil I

Glastonbury, Christine M

Huppert, Laura A

Khanafshar, Elham

Melisko, Michelle E

eScholarship - University of California

UCSFUC San Francisco Previously Published WorksTitleTreatment of Metastatic Melanoma With Leptomeningeal Disease Using Intrathecal Immunotherapy.Permalinkhttps://escholarship.org/uc/item/6131d1j6JournalJCO Oncology Practice, 16(11)ISSN2688-1527AuthorsHuppert, Laura AMelisko, Michelle EGlastonbury, Christine Met al.Publication Date2020-11-01DOI10.1200/op.20.00146 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaThe Treatment of Metastatic Melanoma with Leptomeningeal Disease using Intrathecal Immunotherapy Laura A. Huppert1, Michelle E. Melisko1, Christine M. Glastonbury2, Elham Khanafshar3, Adil I. Daud11 Division of Hematology/Oncology, Department of Medicine, University of California,San Francisco, San Francisco CA 941432 Division of Neuroradiology, Department of Radiology, University of California, San Francisco, San Francisco CA 941433 Department of Pathology, University of California, San Francisco, San Francisco CA 94143Laura A. Huppert MDHematology/Oncology FellowUniversity of California, San Francisco1600 Divisadero Street, Rm A741San Francisco CA 94113Laura.huppert@ucsf.eduMichelle E. Melisko, MDProfessor of MedicineUniversity of California, San Francisco1600 Divisadero StreetSan Francisco CA 94113Christine M Glastonbury, MBBSProfessor of Radiology, Otolaryngology-Head and Neck Surgery and Radiation OncologyUniversity of California, San Francisco505 Parnassus Avenue, Rm M-392San Francisco CA 94143-0628Christine.glastonbury@ucsf.eduElham Khanafshar, MD MSProfessor of PathologyUCSF Department of Pathology1825 4th Street, Room L2181HSan Francisco, CA 94143Elham.khanafshar@ucsf.eduCorresponding Author:Adil I. Daud, MBBSProfessor of Medicine and DermatologyUniversity of California, San Francisco1600 Divisadero Street, Rm A741San Francisco CA 94113Email: Adil.daud@ucsf.edu Tel: 415 353 7392Background:Leptomeningeal disease (LMD) is a devastating complication of metastatic malignancy. Patients with LMD generally present with acute to subacute neurologic deficits that can be quite debilitating. Median survival from time of diagnosis is 3-4 months for solid oncology patients1. Cancer immunotherapy with checkpoint inhibitors (CPIs) has revolutionized cancer treatment, but there is little data about the efficacy of CPIs for treatment of LMD. Several case reports describe clinical improvement in patients with LMD treated with intravenous (IV) CPIs2,3. Preliminary data from a phase II clinical trial suggests that IV pembrolizumab has promising activity for patients with solid tumor malignancies and LMD4, and two other phase II clinical trials are currently underway evaluating IV pembrolizumab monotherapy (NCT03091478) and IV ipilimumab/nivolumab combination therapy (NCT02939300). One potential issue with IV CPI administration is that these monoclonal antibodies are large (>140,00 Da), and thus they may not effectively cross the blood brain barrier. Therefore, one hypothesis is that intrathecal (IT) CPI administration may be a more reliable and efficacious method of drug delivery. Here, we describe the use of IT immunotherapy in two patients with metastatic melanoma and LMD. Case Presentations:Patient One: 49M initially diagnosed with stage III unresectable melanoma of the cutaneous upper back in 2013, now with metastatic disease including LMD since June 2019. He was initially treated with PO dabrafenib/trametinib and IV ipilimumab/nivolumab, but he had radiographic progression of disease (Figure 1A/B) and CSF cytology confirmed the presence of malignant cells (Figure 1C). Therefore, in September 2019 he was started on a combination of IV and IT nivolumab (240mg IVnivolumab and 20mg IT nivolumab q14 days), which he tolerated well. After three cycles of IV/IT nivolumab, repeat MRI brain in October 2019 showed a decrease in the extent of LMD and intraparenchymal metastatic disease (Figure 1D/E) and CSF cytology was benign. Clinically, his seizures and balance improved and his speech was stable. Patient Two: 39F initially diagnosed with stage IIIA melanoma of the right posteriorthigh in 2007, who subsequently developed stage III recurrent disease in 2016. She underwent surgical resection and was started on IV pembrolizumab, but this was stopped due to pneumonitis four months later. Instead, she started PO dabrafenib/trametinib which she continued until progression of disease in September 2018, prompting switch to encorafenib/binimetinib. However, in October 2019, she developed left eye blurriness and left arm numbness. Brain MRI showed several 1cm brain metastases and subtle LMD (Figure 2A), which was confirmed with positive CSF cytology (Figure 2B). Therefore, she was switched back to dabrafenib/trametinib and also started on 20mg IT nivolumab q14 days. She experienced mild headaches with each IT infusion, but otherwise tolerated it well. After three cycles of IT nivolumab, repeat brain MRI in December 2019 showed possible subtle progression of LMD (Figure 2C), although comparison was limited by differences in MRI technique. CSF cytology was now benign and clinically she reported improvement in her visual symptoms. Discussion:This is the first published case report to our knowledge that describes the use of IT immunotherapy in two patients. Both patients tolerated IT nivolumab without notable side effects, and Patient One had a particularly impressive radiographic andclinical response to treatment. These cases highlight the potential benefit of IT immunotherapy, and suggest the need for future clinical trials to evaluate the safety and efficacy of this drug administration strategy. Currently, there is a Phase I clinical trial underway at MD Anderson studying the safety of IV/IT nivolumab in patients with cutaneous or uveal melanoma and LMD (NCT03025256), with results not yet reported. In addition, it will be important to study the safety and efficacy of IT immunotherapy in other primary cancer types. We are hopeful that IT immunotherapy will be a tolerable, effective, and durable treatment option for patients with solid tumor malignancies and LMD.Figure 1. Patient One: Brain MRI and CSF cytology before and after IT nivolumab therapyPatient One: Pre IV/IT nivolumabA   B   CPatient One: Post C3 IV/IT nivolumabD   E Patient One: Pre IV/IT nivolumabA) Coronal T1 post-contrast MRI and (B) Axial FLAIR images from September 2019 before initiation of IV/IT nivolumab. There is extensive linear and nodular leptomeningeal enhancement involving the right frontal sulci which is associated with FLAIR hyperintense marked right frontal edema. Small contralateral parenchymal metastases are also evident. (C) CSF cytology from July 2019 prior to initiation of IV/IT nivolumab. This 600X image shows anenlarged nucleus with prominent nucleoli on the right in comparison with an adjacent mature lymphocyte on the left. Patient One: Post C3 IV/IT nivolumab(D) Coronal T1 post-contrast MRI and (E) Axial FLAIR images from October 2019 after three cycles of IV/IT nivolumab. There is decrease in the extent of leptomeningeal enhancement andmarked decrease in of the right frontal edema and mass effect. There is also a decrease in sizeof the left superior temporal gyrus parenchymal metastasis.Figure 2. Patient Two: Brain MRI and CSF cytology before and after IT nivolumab therapyPatient Two: Pre IT nivolumab           A   B Patient Two: Post C3 IT nivolumabC   Patient Two: Pre IT nivolumab(A) Sagittal T1 post-contrast MRI from October 2019 before initiation of IT nivolumab. There is intracranial metastatic disease and subtle LMD. MRI taken using 1.5T magnet, shown is a 3D BRAVO T1 cut. (B) CSF cytology from October 2019 prior to initiation of IT nivolumab. This 600X image shows a single epithelioid neoplastic cell with pigmented cytoplasm, enlarged nuclei, and prominent nucleoli in comparison with an adjacent mature lymphocyte on the left.Patient Two: Post C3 IT nivolumab(C) Sagittal T1 post-contrast MRI from December 2019 after three cycles of IT nivolumab. MRI taken using a 3T magnet, shown is a 3D CUBE T1 FS image. The difference in coloration between the images is due to differences in MRI technique. REFERENCES1 Wang, N., Bertalan, M. S., & Brastianos, P. K. (2018). Leptomeningeal metastasis from systemic cancer: review and update on management. Cancer, 124(1), 21-35.2 Gion, M., Remon, J., Caramella, C., Soria, J. C., & Besse, B. (2017). Symptomatic leptomeningeal metastasis improvement with nivolumab in advanced non-small cell lung cancer patient. Lung Cancer, 108, 72-74.3 Bot, I., Blank, C. U., & Brandsma, D. (2012). Clinical and radiological response of leptomeningeal melanoma after whole brain radiotherapy and ipilimumab. Journal of neurology, 259(9), 1976-1978.4 Brastianos, P., Prakadan, S., Alvarez-Breckenridge, C., Quant Lee, E., Tolanev, S, … & Sullivan, R (2019). Phase II Study of Pembrolizumab in Leptomeningeal Carcinomatosis. ASCO Meeting 2019.

Treatment of Metastatic Melanoma With Leptomeningeal Disease Using Intrathecal Immunotherapy.

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