MEK-inhibitors in treatment of Langerhans cell histiocytosis
https://doi.org/10.21682/2311-1267-2022-9-3-42-47
Abstract
Background. There are increasing data of targeted therapy efficacy of different types of Langerhans cell histiocytosis (LCH) with inhibitors of BRAF-specific serin-threonine kinase (BRAF-inhibitors) in cases with BRAF V600E mutation published last years. At the same time there are no published data of use of inhibitors of MAPK/ERK pathway (MEK-inhibitors) in pediatric patients with BRAF-negative forms of LCH.
Purpose of the study is to evaluate efficacy and safety of MEK-inhibitor (cobimetinib) in eight pediatric BRAF V600E-negative refractory LCH patients.
Materials and methods. The study included 8 children with various forms of LCH. All patients received therapy according to the LCH-IV protocol and were diagnosed with progression of LCH during or after termination of the treatment. The response to the therapy was assessed in accordance with the international scale Response Evaluation Criteria in Solid Tumors (RECIST v.1.1). The assessment of the toxicity was performed in accordance with the international scale of Common Terminology Criteria for Adverse Events (CTCAE v.5.0).
Results. Complete response was not achieved in any patient. Partial response was established in 5 cases. One patient was diagnosed with disease progression in three months after termination of the therapy. The incidence of adverse events was high.
Conclusion. Cobimetinib therapy is effective in BRAF V600E-negative refractory pediatric LCH patients. The response to the treatment can be delayed. All cases of the toxicity were dose depended and successfully resolved after dose correction. Further research is needed to define duration of treatment and optimal dosage.
About the Authors
E. A. Burtsev
Morozovskaya Children’s Clinical Hospital, Department of Health in Moscow
Russian Federation
Russian Federation
Hematologist HSCT and BMT Department. SPIN-code: 7823-8533
1/9 4th Dobryninskiy Per., Moscow, 119049
G. O. Bronin
Morozovskaya Children’s Clinical Hospital, Department of Health in Moscow
Russian Federation
Russian Federation
Cand. of Sci. (Med.), Docent, Hematologist, Head of the HSCT and BMT Department. SPIN-code: 6485-2648
1/9 4th Dobryninskiy Per., Moscow, 119049
References
1. Rodriguez-Galindo C., Allen C.E. Langerhans cell histiocytosis. Blood. 2020;135(16):1319–31. doi: 10.1182/blood.201900093.
2. Stålemark H., Laurencikas E., Karis J., Gavhed D., Fadeel B., Henter J.-I. Incidence of Langerhans cell histiocytosis in children: A population-based study. Pediatr Blood Cancer. 2008;51(1):76–81. doi: 10.1002/pbc.21504.
3. Lahey M.E. Histiocytosis x--an analysis of prognostic factors. J Pediatr. 1975;87(2):184–9. doi: 10.1016/s0022-3476(75)80576-2.
4. Gadner H., Heitger A., Grois N., Gatterer-Menz I., Ladisch S. Treatment strategy for disseminated langerhans cell histiocytosis. Med Pediatr Oncol. 1994;23(2):72–80. doi: 10.1002/mpo.2950230203.
5. Valiev T.T., Makhonova L.A., Kovrigina A.M., Sholokhova E.N., Tupitsyn N.N., Serebryakova I.N., Mentkevich G.L. Case of congenital Langerhans cells histiocytosis in an infant. Onkogematologiya = Oncohematology. 2011;6(2):19–22. (In Russ.) doi: 10.17650/1818-8346-2011-6-2-19-22.
6. Volkova E.N., Bronin G.O., Vyisotskaya T.A., Finogenova N.A., Tiganova O.A., Nepokulchitskaya N.V. Kovaleva O.L., Timakov A.M., Fetisova L.Y., Motina A.G., Lugovoy L.I., Fuks O.Y., Malceva M.A., Tomilin I.Y., Chernov V.M., Minkov M., Kondratchik K.L., Rumyantsev A.G. Results of retrospective monocenter study of Langerhans cell histiocytosis in children. Pediatriya. Zhurnal im. G.N. Speranskogo = Pediatria. Journal named after G.N. Speransky. 2009;88(4):33–40. (In Russ.).
7. Gadner H., Grois N., Arico M., Broadbent V., Ceci A., Jakobson A., Komp D., Michaelis J., Nicholson S., Potschger U., Pritchard J., Ladisch S. A randomized trial of treatment for multisystem Langerhans’ cell histiocytosis. J Pediatr. 2001;138(5):728–34. doi: 10.1067/mpd.2001.111331.
8. Gadner H., Grois N., Potschger U., Minkov M., Arico M., Braier J., Broadbent V., Donadieu J., Henter J.-I., McCarter R., Ladisch S. Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood. 2007;111(5):2556–62. doi: 10.1182/blood-2007-08-106211.
9. Gadner H., Minkov M., Grois N., Potschger U., Thiem E., Arico M., Astigarraga I., Braier J., Donadieu J., Henter J.-I., Janka-Schaub G., McClain K.L., Weitzman S., Windebank K., Ladisch S. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood. 2013;121(25):5006–14. doi: 10.1182/blood-2012-09-455774.
10. Minkov M. Multisystem Langerhans Cell Histiocytosis in Children. Pediatric Drugs. 2011;13(2):75–86. doi: 10.2165/11538540-000000000-00000.
11. Minkov M. An update on the treatment of pediatric-onset Langerhans cell histiocytosis through pharmacotherapy. Exp Opin Pharmacother. 2018;19(3):233–42. doi: 10.1080/14656566.2018.1429405.
12. Minkov M. Evolution of treatment of children with Langerhans cell histiocytosis. Pediatriya. Zhurnal im. G.N. Speranskogo = Pediatria. Journal named after G.N. Speransky. 2021;100(3):107–20. (In Russ.) doi: 10.24110/0031-403X-2021-100-3-107-120.
13. Minkov M. Langerhans cell histiocytosis: pragmatic empirism on the road to rational cure. Exp Opin Pharmacother. 2012;13(12):1671–3. doi: 10.1517/14656566.2012.698612.
14. Badalian-Very G., Vergilio J.-A., Degar B.A., MacConaill L.E., Brandner B., Calicchio M.L., Kuo F.C., Ligon A.H., Stevenson K.E., Kehoe S.M., Garraway L.A., Hahn W.C., Meyerson M., Fleming M.D., Rollins B.J. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010;116(11):1919–23. doi: 10.1182/blood-2010-04-279083.
15. Brown N.A., Furtado L.V., Betz B.L., Kiel M.J., Weigelin H.C., Lim M.S., Elenitoba-Johnson K.S.J. High prevalence of somatic MAP2K1 mutations in BRAF V600E-negative Langerhans cell histiocytosis. Blood. 2014;124(10):1655–8. doi: 10.1182/blood-2014-05-577361.
16. Yaeger R., Corcoran R.B. Targeting Alterations in the RAF-MEK Pathway. Cancer Discov. 2019;9(3):329–41. doi: 10.1158/2159-8290.CD-18-1321.
17. Greaves W.O., Verma S., Patel K.P., Davies M.A., Barkoh B.A., Galbincea J.M., Yao H., Lazar A.J., Aldape K.D., Medeiros L.J., Luthra R. Frequency and Spectrum of BRAF Mutations in a Retrospective, Single-Institution Study of 1112 Cases of Melanoma. J Mol Diagn. 2013;15(2):220–6. doi: 10.1016/j.jmoldx.2012.10.002.
18. Hodis E., Watson I.R., Kryukov G.V., Arold S.T., Imielinski M., Theurillat J.-P., Nickerson E., Auclair D., Liren L., Place C., Dicara D., Ramos A.H., Lawrence M.S., Cibulskis K., Sivachenko A., Voet D., Saksena G., Stransky N., Onofrio R.C., Winckler W., Ardlie K., Wagle N., Wargo J., Chong K., Morton D.L., Stemle-Hale K., Chen G., Noble M., Meyerson M., Ladbury J.E., Davies M.A., Gershenwald J.E., Wagner S.N., Hoon D.S.B., Shadendorf D., Lander E.S., Gabriel S.B., Getz G., Garraway L.A., Chin L. A Landscape of Driver Mutations in Melanoma. Cell. 2012;150(2):251–63. doi: 10.1016/j.cell.2012.06.024.
19. Yang S., Liu G. Targeting the Ras/Raf/MEK/ERK pathway in hepatocellular carcinoma. Oncol Lett. 2017;13(3):1041–7. doi: 10.3892/ol.2017.5557.
20. Se W.L., Mukherjee J. Targeting the RAS-RAF-MEK-ERK Signaling Pathway in Gliomas. In: Handbook of Brain Tumor Chemotherapy, Molecular Therapeutics and Immunotherapy, 2018. Pp. 323–332. doi: 10.1016/b978-0-12-812100-9.00022-x/.
21. Chapman P.B., Hauschild A., Robert C., Haanen J.B., Ascierto P., Larkin J., Dummer R., Garbe C., Testori A., Maio M., Hogg D., Lorigan P., Lebbe C., Jouary T., Schadendorf D., Ribas A., O’Day S.J., Sosman J.A., Kirkwood J.M., Eggermont A.M.M., Dreno B., Nolop K., Li J., Nelson B., Hou J., Lee R.J., Flaherty K.T., McArthur G.A. Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation. N Eng J Med. 2011;364(26):2507–16. doi: 10.1056/nejmoa1103782.
22. Ribas A., Daud A., Pavlick A.C., Gonzalez R., Lewis K.D., Hamid O., Gajewski T.F., Puzanov I., Wongchenko M., Rooney I., Hsu J.J., Yan Y., Park E., McArthur G.A. Extended 5-Year Follow-up Results of a Phase Ib Study (BRIM7) of Vemurafenib and Cobimetinib in BRAF-Mutant Melanoma. Clin Cancer Res. 2020;26(1):46–53. doi: 10.1158/1078-0432.ccr-18-4180.
23. Larkin J., Ascierto P.A., Dréno B., Atkinson V., Liszkay G., Maio M., Mondala M., Demidov L., Stroyakovskiy D., Thomas L., Gruz-Merino L., Dutriaux C., Garbe C., Sovak M.A., Chang I., Choong N., Hack S.P., McArthur G.A., Ribas A. Combined Vemurafenib and Cobimetinib in BRAF-Mutated Melanoma. N Eng J Med. 2014;371(20):1867–76. doi: 10.1056/nejmoa1408868.
24. Gong S., Xu D., Zhu J., Zou F., Peng, R. Efficacy of the MEK Inhibitor Cobimetinib and its Potential Application to Colorectal Cancer Cells. Cell Physiol Biochem. 2018;47(2):680–93. doi: 10.1159/000490022.
25. Han J., Liu Y., Yang S., Wu X., Li H., Wang Q. MEK inhibitors for the treatment of non-small cell lung cancer. J Hematol Oncol. 2021;14(1):1. doi: 10.1186/s13045-020-01025-7.
26. Diamond E.L., Durham B.H., Ulaner G.A., Drill E., Buthorn J., Ki M., Bitner L., Cho H., Young R.J., Francis J.H., Rampal R., Lacoture M., Brody L.A., Ozkaya N., Dogan A., Rosen N., Lasonos A., Abdel-Wahab O., Hyman D.M. Efficacy of MEK inhibition in patients with histiocytic neoplasms. Nature. 2019;567(7749):521–4. doi: 10.1038/s41586-019-1012-y.
27. Donadieu J., Piguet C., Bernard F., Barkaoui M., Ouache M., Bertrand Y., Thomas C. A New clinical score for disease activity in Langerhans cell histiocytosis. Pediatr Blood Cancer. 2004;43(7):770–6. doi: 10.1002/pbc.20160.
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For citations:
Burtsev E.A., Bronin G.O. MEK-inhibitors in treatment of Langerhans cell histiocytosis. Russian Journal of Pediatric Hematology and Oncology. 2022;9(3):42-47. (In Russ.) https://doi.org/10.21682/2311-1267-2022-9-3-42-47
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