312
Views
14
CrossRef citations to date
0
Altmetric
Review

Clinical Management of Relapsed/Refractory Hemophagocytic Lymphohistiocytosis in Adult Patients: A Review of Current Strategies and Emerging Therapies

ORCID Icon, , &
Pages 293-304 | Published online: 14 Apr 2021

References

  • Humblet-Baron S, Franckaert D, Dooley J, et al. FN-γ and CD25 drive distinct pathologic features during hemophagocytic lymphohistiocytosis. J Allergy Clin Immunol. 2019;143(6):2215–2226.e7. doi:10.1016/j.jaci.2018.10.068
  • Janka GE, Lehmberg K. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. Hematol Am Soc Hematol Educ Program. 2013;2013(1):605–611. doi:10.1182/asheducation-2013.1.605
  • Yildiz H, Van Den Neste E, Defour JP, Danse E, Yombi JC. Adult haemophagocytic lymphohistiocytosis: a review. QJM. 2020. doi:10.1093/qjmed/hcaa011
  • La Rosée P, Horne AC, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133(23):2465–2477. doi:10.1182/blood.2018894618
  • Miao Y, Zhu HY, Qiao C, et al. Pathogenic gene mutations or variants identified by targeted gene sequencing in adults with hemophagocytic lymphohistiocytosis. Front Immunol. 2019;10:395. doi:10.3389/fimmu.2019.00395
  • Zhang K, Jordan MB, Marsh RA, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult onset familial HLH. Blood. 2011;118(22):5794–5798. doi:10.1182/blood-2011-07-370148
  • Chen X, Wang F, Zhang Y, et al. Genetic variant spectrum in 265 Chinese patients with hemophagocytic lymphohistiocytosis: molecular analyses of PRF1, UNC13D, STX11, STXBP2, SH2D1A, and XIAP. Clin Genet. 2018;94(2):200–212. doi:10.1111/cge.13363
  • Ramos-Casals M, Brito-Zeron P, Lopez-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503–1516. doi:10.1016/S0140-6736(13)61048-X
  • Sepulveda FE, de Saint Basile G. Hemophagocytic syndrome: primary forms and predisposing conditions. Curr Opin Immunol. 2017;49:20–26. doi:10.1016/j.coi.2017.08.004
  • Brisse E, Wouters CH, Matthys P. Advances in the pathogenesis of primary and secondary haemophagocytic lymphohistiocytosis: differences and similarities. Br J Haematol. 2016;174(2):203–217. doi:10.1111/bjh.14147
  • Zhang M, Behrens EM, Atkinson TP, Shakoory B, Grom AA, Cron RQ. Genetic defects in cytolysis in macrophage activation syndrome. Curr Rheumatol Rep. 2014;16(9):439–446. doi:10.1007/s11926-014-0439-2
  • Carvelli J, Piperoglou C, Farnarier C, et al. Functional and genetic testing in adults with HLH reveals an inflammatory profile rather than a cytotoxicity defect. Blood. 2020;136(5):542–552. doi:10.1182/blood.2019003664
  • Terrell CE, Jordan MB. Perforin deficiency impairs a critical immunoregulatory loop involving murine CD8(+) T cells and dendritic cells. Blood. 2013;121(26):5184–5191. doi:10.1182/blood-2013-04-495309
  • Rood JE, Rao S, Paessler M, et al. ST2 contributes to T cell hyperactivation and fatal hemophagocytic lymphohistiocytosis in mice. Blood. 2016;127(4):426–435. doi:10.1182/blood-2015-07-659813
  • Mao H, Tu W, Qin G, et al. Influenza virus directly infects human natural killer cells and induces cell apoptosis. J Virol. 2009;83(18):9215–9222. doi:10.1128/JVI.00805-09
  • Jenkins MR, Rudd-Schmidt JA, Lopez JA, et al. Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time. J Exp Med. 2015;212(3):307–317. doi:10.1084/jem.20140964
  • Vastert SJ, van Wijk R, D’Urbano LE, et al. Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis. Rheumatology (Oxford). 2010;49(3):441–449. doi:10.1093/rheumatology/kep418
  • Kaufman KM, Linghu B, Szustakowski JD, et al. Whole exome sequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphohistiocytosis. Arthritis Rheum. 2014;66(12):3486–3495. doi:10.1002/art.38793
  • Sieni E, Cetica V, Piccin A, et al. Familial hemophagocytic lymphohistiocytosis may present during adulthood: clinical and genetic features of a small series. PLoS One. 2012;7(9):e44649. doi:10.1371/journal.pone.0044649
  • Cetica V, Sieni E, Pende D, et al. Genetic predisposition to hemophagocytic lymphohistiocytosis: report on 500 patients from the Italian registry. J Allergy Clin Immunol. 2016;137(1):188–196.e4. doi:10.1016/j.jaci.2015.06.048
  • Al-Samkari H, Berliner N. Hemophagocytic lymphohistiocytosis. Annu Rev Pathol Mech Dis. 2018;13(1):1.1–1.23. doi:10.1146/annurev-pathol-020117-043625
  • Fazal F, Gupta N, Mittal A, Ray A. Haemophagocytic lymphohistiocytosis in human immunodeficiency virus: a systematic review of literature. Drug Discov Ther. 2020;14(5):226–231. doi:10.5582/ddt.2020.03069
  • Machaczka M, Vaktnäs J, Klimkowska M, Hägglund H. Malignancy-associated hemophagocytic lymphohistiocytosis in adults: a retrospective population-based analysis from a single center. Leuk Lymphoma. 2011;52(4):613–619. doi:10.3109/10428194.2010.551153
  • Ravelli A, Davì S, Minoia F, Martini A, Cron RQ. Macrophage Activation Syndrome. Hematol Oncol Clin North Am. 2015;29(5):927–941. doi:10.1016/j.hoc.2015.06.010
  • Sadaat M, Jang S. Hemophagocytic lymphohistiocytosis with immunotherapy: brief review and case report. J Immunother Cancer. 2018;6(1):49. doi:10.1186/s40425-018-0365-3
  • Laderian B, Koehn K, Holman C, Lyckholm L, Furqan M. Association of hemophagocytic lymphohistiocytosis and programmed death 1 checkpoint inhibitors. J Thorac Oncol. 2019;14(4):e77–e78. doi:10.1016/j.jtho.2018.11.035
  • Moon YW, Hajjar J, Hwu P, Naing A. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J Immunother Cancer. 2015;3(1):51. doi:10.1186/s40425-015-0094-9
  • Put K, Brisse E, Avau A, et al. IDO1 deficiency does not affect disease in mouse models of systemic juvenile idiopathic arthritis and secondary hemophagocytic lymphohistiocytosis. PLoS One. 2016;11(2):e0150075. doi:10.1371/journal.pone.0150075
  • Hayden A, Park S, Giustini D, Lee AY, Chen LY. Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in adults: a systematic scoping review. Blood Rev. 2016;30(6):411–420. doi:10.1016/j.blre.2016.05.001
  • Karras A, Thervet E, Le Meur Y, Baudet-Bonneville V, Kessler M, Legendre C. Successful renal retransplantation after post-transplant lymphoproliferative disease. Am J Transplant. 2004;4(11):1904–1909. doi:10.1111/j.1600-6143.2004.00562.x
  • Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66(9):2613–2620. doi:10.1002/art.38690
  • Debaugnies F, Mahadeb B, Ferster A, et al. Performances of the H-score for diagnosis of hemophagocytic lymphohistiocytosis in adult and pediatric patients. Am J Clin Pathol. 2016;145(6):862–870. doi:10.1093/ajcp/aqw076
  • Chaturvedi V, Marsh RA, Lorenz AZ, et al. T cell activation profiles distinguish hemophagocytic lymphohistiocytosis and early sepsis. Blood. 2020:blood.2020009499. PMID: 33512385. doi:10.1182/blood.2020009499
  • Abdalgani M, Filipovich AH, Choo S, et al. Accuracy of flow cytometric perforin screening for detecting patients with FHL due to PRF1 mutations. Blood. 2015;126(15):1858–1860. doi:10.1182/blood-2015-06-648659
  • Rubin TS, Zhang K, Gifford C, et al. Perforin and CD107a testing is superior to NK cell function testing for screening patients for genetic HLH. Blood. 2017;129(22):2993–2999. doi:10.1182/blood-2016-12-753830
  • Merli P, Gentile L, Quagliarella F, et al. QuantiFERON-TB Gold can help clinicians in the diagnosis of haemophagocytic lymphohistiocytosis. Br J Haematol. 2020;191(2):e64–e67. doi:10.1111/bjh.17001
  • Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain K. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118(15):4041–4052. doi:10.1182/blood-2011-03-278127
  • Ehl S, Astigarraga I, von Bahr Greenwood T, et al. Recommendations for the use of etoposide-based therapy and bone marrow transplantation for the treatment of HLH: consensus statements by the HLH Steering Committee of the Histiocyte Society. J Allergy Clin Immunol Pract. 2018;6(5):1508–1517. doi:10.1016/j.jaip.2018.05.031
  • Trottestam H, Horne A, Arico M, et al.; Histiocyte Society. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011;118(17):4577–4584. doi:10.1182/blood-2011-06-356261
  • La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology Am Soc Hematol Educ Program. 2015;2015(1):190–196. doi:10.1182/asheducation-2015.1.190
  • Daver N, McClain K, Allen CE, et al. A consensus review on malignancy-associated hemophagocytic lymphohistiocytosis in adults. Cancer. 2017;123(17):3229–3240. doi:10.1002/cncr.30826
  • Guangqiang M, Wang Y, Wang J, Wang Z. The DEP regimen is superior to the HLH-1994 regimen as first-line therapy for lymphoma-associated haemophagocytic lymphohistiocytosis. Leuk Lymphoma. 2020. doi:10.1080/10428194.2020.1849671
  • Delavigne K, Bérard E, Bertoli S, et al. Hemophagocytic syndrome in patients with acute myeloid leukemia undergoing intensive chemotherapy. Haematologica. 2014;99(3):474–480. doi:10.3324/haematol.2013.097394
  • Wang Y, Huang W, Hu L, et al. Multicenter study of combination DEP regimen as a salvage therapy for adult refractory hemophagocytic lymphohistiocytosis. Blood. 2015;126(19):2186–2192. doi:10.1182/blood-2015-05-644914
  • Marsh RA, Allen CE, McClain KL, et al. Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer. 2013;60(1):101–109. doi:10.1002/pbc.24188
  • Yuan L, Kan Y, Meeks JK, Ma D, Yang J. 18F-FDG PET/CT for identifying the potential causes and extent of secondary hemophagocytic lymphohistiocytosis. Diagn Interv Radiol. 2016;22(5):471–475. doi:10.5152/dir.2016.15226
  • Zheng Y, Hu G, Liu Y, et al. The role of 18F-FDG PET CT in the management of patients with secondary haemophagocytic lymphohistiocytosis. Clin Radiol. 2016;71(12):1248–1254. doi:10.1016/j.crad.2016.05.011
  • Henter JI, Samuelsson-Horne A, Aricò M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100(7):2367–2373. doi:10.1182/blood-2002-01-0172
  • Horne A, Janka G, Maarten Egeler R, et al. Haematopoietic stem cell transplantation in haemophagocytic lymphohistiocytosis. Br J Haematol. 2005;129(5):622–630. doi:10.1111/j.1365-2141.2005.05501.x
  • Bergsten E, Horne A, Hed Myrberg I, et al. Stem cell transplantation for children with hemophagocytic lymphohistiocytosis: results from the HLH-2004 study. Blood Adv. 2020;4(15):3754–3766. doi:10.1182/bloodadvances.2020002101
  • Li Z, Wang Y, Wang J, Zhang J, Wang Z. Haploidentical hematopoietic stem cell transplantation for adult patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Leuk Lymphoma. 2018;59(1):77–84. doi:10.1080/10428194.2017.1330467
  • Oliansky DM, Czuczman M, Fisher RI, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of diffuse large B cell lymphoma: update of the 2001 evidence-based review. Biol Blood Marrow Transplant. 2011;17(1):20–47. doi:10.1016/j.bbmt.2010.07.008
  • Wang J, Wang Y, Wu L, Zhang J, Lai W, Wang Z. PEG-aspargase and DEP regimen combination therapy for refractory Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. J Hematol Oncol. 2016;9(1):84. doi:10.1186/s13045-016-0317-7
  • Zhao Y, Shi J, Li X, et al. Salvage therapy with dose-escalating ruxolitinib as bridge to allogeneic stem cell transplantation for refractory hemophagocytic lymphohistiocytosis. Bone Marrow Transplant. 2020;55(4):824–826. doi:10.1038/s41409-019-0577-2
  • Locatelli F, Jordan MB, Allen CE, et al. Emapalumab in Children with primary hemophagocytic lymphohistiocytosis. N Engl J Med. 2020;382(19):1811–1822. doi:10.1056/NEJMoa1911326
  • Vallurupalli M, Berliner N. Emapalumab for the treatment of relapsed/refractory hemophagocytic lymphohistiocytosis. Blood. 2019;134(21):1783–1786. doi:10.1182/blood.2019002289
  • Meyer LK, Verbist KC, Albeituni S, et al. JAK/STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation. Blood. 2020;136(6):657–668. doi:10.1182/blood.2020006075
  • Sin JH, Zangardi ML. Ruxolitinib for secondary hemophagocytic lymphohistiocytosis: first case report. Hematol Oncol Stem Cell Ther. 2019;12(3):166–170. doi:10.1016/j.hemonc.2017.07.002
  • Wang J, Wang Y, Wu L, et al. Ruxolitinib for refractory/relapsed hemophagocytic lymphohistiocytosis. Haematologica. 2020;105(5):e210. doi:10.3324/haematol.2019.222471
  • Ahmed A, Merrill SA, Alsawah F, et al. Ruxolitinib in adult patients with secondary haemophagocytic lymphohistiocytosis: an open-label, single-centre, pilot trial. Lancet Haematol. 2019;6(12):e630–e637. doi:10.1016/S2352-3026(19)30156-5
  • Boonstra PS, Ahmed A, Merrill SA, Wilcox RA. Ruxolitinib in adult patients with secondary hemophagocytic lymphohistiocytosis. Am J Hematol. 2021;96(4). doi:10.1002/ajh.26091
  • Wang J, Wang Z. Multicenter study of ruxolitinib combined DEP regimen as a salvage therapy for refractory/relapsed hemophagocytic lymphohistiocytosis. Blood. 2019;134(Supplement_1):1042. doi:10.1182/blood-2019-130980
  • Kim ST, Cristescu R, Bass AJ, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med. 2018;24(9):1449–1458. doi:10.1038/s41591-018-0101-z
  • Liu P, Pan X, Chen C, et al. Nivolumab treatment of relapsed/refractory Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults. Blood. 2020;135(11):826–833. doi:10.1182/blood.2019003886
  • Saarela M, Senthil K, Jones J, et al. Hemophagocytic lymphohistiocytosis in 2 patients with multiple sclerosis treated with alemtuzumab. Neurology. 2018;90(18):849–851. doi:10.1212/WNL.0000000000005420
  • So MW, Koo BS, Kim YJ, Kim YG, Lee CK, Yoo B. Successful rituximab treatment of refractory hemophagocytic lymphohistiocytosis and autoimmune hemolytic anemia associated with systemic lupus erythematosus. Mod Rheumatol. 2014;24(5):855–857. doi:10.3109/14397595.2013.874740
  • Henzan T, Nagafuji K, Tsukamoto H, et al. Success with infliximab in treating refractory hemophagocytic lymphohistiocytosis. Am J Hematol. 2006;81(1):59–61. doi:10.1002/ajh.20462
  • Lorenz G, Schul L, Schraml F, et al. Adult macrophage activation syndrome-haemophagocytic lymphohistiocytosis: ‘of plasma exchange and immunosuppressive escalation strategies’ - a single centre reflection. Lupus. 2020;29(3):324–333. doi:10.1177/0961203320901594