Background: Hemophagocytic Lymphohistiocytosis (HLH), a rare but potentially fatal syndrome of immune hyperactivation, may be an under-recognized immune-related adverse event (irAE). Unlike other irAEs, HLH triggered by immune checkpoint blockade is not well described; no particular diagnostic guidelines and treatment regimens exist. The HLH-2004 criteria remain as the common diagnostic guide. For the treatment of HLH, various combinations of chemotherapeutic, immunosuppressive and glucocorticoid agents are used. Case presentation: We report a case of HLH in a 58-year-old metastatic melanoma patient who was undergoing immune checkpoint blockade with pembrolizumab, a programmed cell death-1 (PD-1) receptor inhibitor. The patient presented with fever, upper normal sized spleen, anemia, thrombocytopenia, hypertriglyceridemia, hyperferritinemia, reduced NK cell activity and elevated sCD163 levels, fulfilling the Histiocyte Society HLH-2004 diagnostic criteria. Our patient was successfully treated with oral prednisone (1 mg/kilogram/day), suggesting that HLH from immune checkpoint inhibitors may respond to steroids alone. Conclusion: Early diagnosis and treatment of HLH are critical to avoid progressive tissue damage, organ failure and possibly death. HLH should be suspected in clinical presentations with fever, cytopenias and hyperinflammatory markers. HLH in the setting of immune checkpoint blockade may be treated with steroids only but further evidence is required. Keywords: Hemophagocytic lymphohistiocytosis, HLH, Immune checkpoint inhibitors, Checkpoint blockade, Pembrolizumab, Ipilimumab, Nivolumab, iRAE, Natural killer cells, sCD163, PD-1, PDL-1, Macrophage activation syndrome, Cytokine release syndrome, CAR T, BiTe Background Clinical features usually include those listed in As immunotherapy continues to evolve and show prom- HLH-2004 criteria (Table 1)[2, 3]. ise in the treatment of various cancers, timely diagnosis In primary HLH, which manifests mainly in childhood, and effective management of immune-related adverse mutations occur in genes that encode essential protein events (irAEs) become more important. Some irAEs components of the cytotoxic machinery of T lympho- such as hemophagocytic lymphohistiocytosis (HLH) can cytes and natural killer (NK) cells. Altered genes be systemic and deadly. involved in immunodeficiency syndromes also constitute Hemophagocytic Lymphohistiocytosis refers to a po- the causes of primary HLH. Acquired HLH, with or tentially fatal clinical syndrome of hyperinflammation without genetic disorders, may be due to infectious and progressive immune-mediated organ damage due to (bacterial, fungal, parasitic and viral) or non-infectious over-stimulated but ineffective immune response . etiologies and triggers (malignancies, autoimmune disor- ders, and drugs) . The exact pathophysiology of HLH varies depending * Correspondence: firstname.lastname@example.org on the cause and trigger . Based mainly on the patho- Inova Center for Personalized Health, Inova Schar Cancer Institute, 3225 physiology of primary HLH, defective granule-mediated Gallows Rd, 7th Floor, Tower D, Fairfax, VA 22031, USA cytotoxicity of cytotoxic T lymphocytes (CTLs) and Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sadaat and Jang Journal for ImmunoTherapy of Cancer (2018) 6:49 Page 2 of 5 Table 1 Histiocyte Society HLH-2004 diagnostic criteria [2, 3] may add to the effects of malignancy on immune homeostasis [6, 7]. The diagnosis HLH requires that either 1 or 2 below are fulfilled: Removal of normal control on important immune sys- (1) A molecular diagnosis consistent with HLH: Pathological mutations of PRF1, UNC13D, STXBP1, RAB27A, STX11, SH2D1A, or XIAP tem pathways such as PD-1, PDL-1 and CTLA-4, may result in unique irAEs (eg, dermatitis, ophthalmological OR a disorders, endocrinopathies, myocarditis, pericarditis, (2) Diagnostic criteria for HLH fulfilled (5 out of the 8 criteria below): vasculitis, colitis, hepatitis, nephritis and pneumonitis) (A) Initial diagnostic criteria . These irAEs are fairly well described and usually, � Fever 38·5 °C or more manageable with the administration of high-dose gluco- � Splenomegaly corticoids . The incidence of HLH due to immuno- � Cytopenias (affecting at least 2 of 3 cell lineages in the peripheral therapy, however, has been rarely reported. The few blood): reported cases had different diagnostic and therapeutic ○ Hemoglobin < 90 g/L (in infants < 4 weeks: hemoglobin approaches with variable outcomes. Here we report a < 100 g/L) case of HLH triggered by pembrolizumab that was ○ Platelets < 100 × 10 /L treated successfully with high-dose glucocorticoids. We ○ Neutrophils < 1.0 × 10 /L also present a brief review of literature regarding the HLH cases due to immunotherapy, the dilemmas in � Hypertriglyceridemia and/or hypofibrinogenemia: diagnosing HLH, and the therapeutic hurdles in man- ○ Fasting triglycerides ≥3.0 mmol/L (i.e., ≥ 265 mg/dL) aging HLH. ○ Fibrinogen ≤1.5 g/L � Hemophagocytosis in bone marrow or spleen or lymph nodes or liver Case presentation (B) New diagnostic criteria A 58-year-old man with metastatic melanoma was ad- � Low or absent NK-cell activity mitted to the hospital with 3-day history of high fever � Ferritin ≥500 mg/L (up to 104.7 degrees Fahrenheit), nausea and arthralgias 31 days after receiving 6 doses of pembrolizumab (2 mg � Soluble CD25 (i.e., soluble IL-2 receptor) ≥ 2400 U/mL per kilogram of body weight). Initial workup revealed Supportive criteria include neurologic symptoms, cerebrospinal pleocytosis, conjugated hyperbilirubinemia and transaminitis, hypoalbuminemia, hyponatremia, anemia (hemoglobin level, 9.9 g/dL [normal: 13 to 17 g/ elevated D-dimers, and lactate dehydrogenase. The absence of hemophagocytosis dL]) with low normal reticulocyte (0.6%, [normal: 0.5 to (in the bone marrow) does not exclude a diagnosis of HLH New data show normal variation by age. Level should be compared with 2%]), thrombocytopenia (platelet level 101 × 103/microL age-related norms [normal: 140-400 × 103/microL]), hypertriglyceridemia (triglycerides level, 309 mg/dL [normal: 0–149 mg/dL]), natural killer (NK) cells is considered the main abnor- and marked elevation in ferritin (> 40,000.00 ng/mL mality that causes HLH. Since CTLs and NK cells can- [normal: 30–400 ng/mL]) and lactate dehydrogenase not insert perforin channels into the membranes of (2762 U/L [normal: 140–480 U/L]). Computed tomog- antigen presenting cells (eg, macrophages and histio- raphy depicted the size of spleen in upper normal cytes) and deliver granzymes, osmolysis and apoptosis of (13 cm). Extensive lab and radiologic work up to identify the antigen presenting cells do not occur. With persist- any infectious agents was unremarkable. Study of natural ent antigenic stimulation of CTLs and NK cells by the killer (NK) cells showed decreased NK cell function. Sol- antigen presenting cells, an abundant release of uble CD163 (sCD163) level was 6384 ng/mL (Reference cytokines ensues. The cytokine storm creates a systemic range: 387–1785 ng/mL) (Table 2). inflammation that can cause tissue destruction, progres- Patient was treated with high-dose glucocorticoids sive organ failure and death. Activated macrophages may (oral prednisone administered at 1 mg per kilogram per engulf blood cells and create hemophagocytosis , the day) within 24 h after admission. Rapid resolution of pathologic feature of HLH. fever, nausea and gradual improvement in his arthralgia Malignancy-associated HLH (M-HLH) refers to HLH were noted. Patient’s anemia and thrombocytopenia that occurs due to malignancy or happens during cancer improved after administration of glucocorticoids, treatment. The incidence of M-HLH is cited as 1% with therefore, we did not perform bone marrow biopsy. a median survival of 1.5–2.5 months . The relatively After 5 weeks of high-dose glucocorticoids, steroid dose recent use of immunotherapies (eg, immune checkpoint was tapered over 7 weeks without recurring symptoms. inhibitors, bispecific mono-clonal antibody and bispeci- Pembrolizumab was permanently discontinued. Patient fic T-cell engagers [BiTe]; chimeric antigen receptor achieved complete response in his metastatic melanoma T-cell therapies [CAR T], dendritic vaccines, and immu- for approximately 1 yr and then developed new nomodulatory drugs) in the treatment of various cancers metastases. Sadaat and Jang Journal for ImmunoTherapy of Cancer (2018) 6:49 Page 3 of 5 Table 2 Results of immunologic study of natural killer cells (NK a positive predictive value of 93% but sensitivity of cells) and sCD163 levels this finding was low (46%) . A. Natural Killer (NK) Cell Function Our diagnosis was confirmed by immunological studies showing decreased NK cell function and high E:T Ratio Result Cytotoxicity Reference Range sCD163 levels. As a hemoglobin-haptoglobin scaven- 50:1 5% Low (> = 20) ger receptor, sCD163 is a lineage marker indicating 25:1 2% Low (> = 10) macrophage expansion and hyperactivation , which 12:1 2% Low (> = 5) may be a useful marker for diagnosis of HLH and re- 6:1 1% (> = 1) lated disorders . Soluble IL-2 (also known as NK Lytic Units 0.1 Low (> = 2.6) sCD25) is a helpful marker for diagnosis and disease severity but not widely available . CD16/56% positive 4% Low (7–31) Bone marrow, lymph node, liver, spleen and even skin Interpretation: Decreased NK cell function. biopsies to detect hemophagocytosis and/or lymphocyto- sis can be used as supportive markers . However, it B. sCD163 Level 6384 ng/mL (387–1785 ng/mL) is well known that the presence of hemophatocytosis or Immunologic study was conducted in Diagnostic Immunology Lab, Cincinnati lymphocytosis is neither specific nor sensitive for HLH Children’s Hospital [1, 16]. Initial biopsy can be negative and repeat biopsies are required for follow up . Daver and colleagues Discussion further argue that hemophagocytosis is not pathogno- A. Diagnostic dilemmas monic for HLH and may cause delayed or missed diag- Daver et al. state that less than 50% of adults with nosis . With sufficient clinical and lab criteria, M-HLH received HLH-directed therapy because of lack identifiable cause of HLH, and significant improvement of awareness and missed diagnosis of this condition in in our patient’s condition, we forewent bone marrow bi- adult patients with malignancies in their center . High opsy . However, our conservative approach may not morbidity and mortality due to HLH is partially attrib- be advisable for most patients unless expert panels iden- uted to delay in diagnosis. The rarity of the syndrome, tify criteria with defined diagnostic weight and value for non-specific and overlapping clinical picture with that of M-HLH and other sub-types. infection and sepsis, lack of validated criteria, and scar- city of diagnostic tools such as bone marrow biopsy, mu- B. Challenges in treatment tation testing and molecular assays are among the Specific HLH treatment guidelines based on randomized contributing factors. Online H-Score compiled by Fardet trials do not exist . Management of initial phases of gen- et al.  and a list of criteria developed by a panel of etic and acquired HLH is similar and in addition to sup- experts in the Delphi study  are examples of at- portive therapy, specific treatment is aimed at control of tempts to move towards precision and avoidance of de- cytotoxicity and immunomodulation. Based on HLH-94 lays in diagnosing HLH. and 2004 protocols, high-dose glucocorticoids, etoposide, Our patient presented with fever, upper normal sized methotrexate and cyclosporine are major components of spleen, cytopenias affecting RBC and platelets, hypertri- the treatment regimen [19–21]. The efficacy and outcome glyceridemia, high ferritin, low NK cell activity, thereby of these protocols in adults have not been evaluated, al- fulfilling the diagnostic criteria for HLH (Table 1). This though a global analysis of adult case reports indicates that patient was diagnosed with metastatic melanoma 2 years etoposide-containing regimens improve survival in cancer prior to receiving pembrolizumab, therefore it was un- and infection (71–75%) more than in autoimmune diseases likely that metastatic melanoma itself triggered HLH. In (57%) . Patients with genetic HLH may remain on main- the absence of an infectious cause, we concluded that tenance therapy until allogeneic hematopoietic cell trans- HLH was related to pembrolizumab. plantation. In acquired HLH patients, the underlying cause High fever and hyperferritinemia prompted us to needs to be treated . Additionally, intravenous immuno- consider HLH in our diagnostic workup. Hyperferriti- globulin therapy (estimated survival rate increase to 59– nemia is a non-specific marker indicating inflamma- 75%) and plasma exchange (survival of approximately 80%) tory, infectious, hepatocellular, renal, metabolic and have been tried. Biological treatments (eg, rituximab, inflixi- many other processes. However, Carl et al. report that mab and etanercept), anti-TNF drugs, anti-interleukin-1r ferritinemia greater than 10,000 μg/L had a sensitivity (anakinra), anti-interleukin-6 (tocilizumab), and B-cell de- of 90% and a specificity of 96% for HLH diagnosis pleting drugs (rituximab, belimumab) have shown varying . Elevated ferritin levels are also implicated in degrees of clinical efficacy in different HLH subtypes [1, 3]. prognosis. Grangé and colleagues cite that hyperferri- Alemtuzumab, IFN-gamma inhibitor (NI-0501), and Janus tinemia greater than 4780 μg/L predicted death with kinase 1 (JAK1)/JAK2 inhibitor (ruxolitinib) are novel Sadaat and Jang Journal for ImmunoTherapy of Cancer (2018) 6:49 Page 4 of 5 therapeutic agents either in trials or approved for HLH malignancies [27, 28]. T cell–engaging therapies harness treatment . the cell-mediated immune response to attack cancer The treatment of HLH requires careful analysis of cells without the involvement of the major histocompati- underlying trigger, patient’s performance status, organ bility complex. The main challenge of T cell-engaging functions, and concomitant therapies. In case of therapies, however, has been toxicity. The most common M-HLH, the need for such analysis is even more crucial toxicity is the cytokine release syndrome (CRS), a group . Treatment guidelines or trials are non-existent for of inflammatory symptoms due to cytokine elevations management of M-HLH and HLH as an irAE. A pro- associated with T cell engagement and proliferation. CRS spective study of 63 patients in China used combination symptoms can range from mild and flulike to a severe of chemotherapy with liposomal doxorubicin, etoposide inflammatory syndrome, including vascular leak, and methylprednisolone as a salvage therapy for adult hypotension, pulmonary edema, and coagulopathy, patients with refractory HLH. The regimen resulted in which could lead to multi-organ failure, similar to HLH complete remissions in 27% and partial remissions in and MAS. Steroids and direct targeting of elevated cyto- 49% of the patients . kines have shown variable success in the treatment of CRS patients . C. HLH due to immunotherapy HLH has also been reported in 2 patients with mul- HLH has rarely been reported in patients receiving tiple sclerosis after treatment with alemtuzumab , a immune checkpoint inhibitors. Shah et al. reported a humanized monoclonal antibody. The first patient, a patient who developed HLH after 9 months of pem- mid-20s female, died despite treatment with IV cortico- brolizumab treated with etoposide and dexamethasone steroids and a molecular adsorbent recirculation system . In contrast, our case was successfully treated procedure. The second patient, a 28-year-old male, was with glucocorticoids only suggesting that HLH from treated with rituximab and corticosteroids. immune checkpoint inhibitors may respond to ste- roids alone. Conclusion Satzger et al. reported a 26-year-old female who devel- Our case and other reported cases indicate that HLH oped HLH during treatment with nivolumab plus ipili- may occur due to immunotherapy. HLH, CRS and MAS mumab for metastatic melanoma. Their patient was have been reported with different immunotherapeutic treated with prednisone 2 mg/kg/day, which was tapered agents. Significant morbidity and mortality due to these to 1 mg/kg/day after a week and mycophenolate mofetil systemic inflammatory syndromes can impact the use was started 360 mg b.i.d with a subsequent increase to and development of immunotherapeutic agents. 720 mg b.i.d . HLH can lead to progressive organ failure, hence early Malissen et al. reported 3 cases of “Macrophage Acti- diagnosis and treatment are important. The case reports vation Syndrome” (a term traditionally reserved for HLH highlight the need for diagnostic and therapeutic guide- due to rheumatologic disorders, namely systemic juven- lines as well as randomized trials to assess HLH man- ile idiopathic arthritis). The first patient, a 77-year-old agement especially in adults with cancer. Optimal male with metastatic melanoma who received Nivolu- treatment for HLH likely caused by immune checkpoint mab therapy, died despite treatment with steroids inhibitors and other immunotherapeutic agents is not (0.5 mg/kg). Second melanoma patient, 42-year-old male known. As suggested by our case and cases by other au- receiving ipilimumab after initial treatment with nivolu- thors, early intervention with high dose steroids alone mab, recovered with systemic corticotherapy and antibi- may be successful in the treatment of HLH from immune otics. The third patient, 81-year-old male with Merkel checkpoint blockade. Moreover, to avoid missed or de- Cell carcinoma developed MAS (HLH) shortly after the layed diagnosis, primary, emergency and critical care first dose of avelumab and died despite high-dose teams may benefit from enhanced knowledge regarding steroids . the diagnosis and treatment of irAEs, including HLH and Takeshita and colleagues reported hemophagocytic CRS. HLH should be in the differential diagnosis of pa- syndrome, interstitial pneumonia, and probable Ste- tients presenting with fever, cytopenias and any other vens–Johnson syndrome in a 63-year-old woman with signs or markers of a hyperinflammatory status. stage IV squamous non-small cell lung cancer with nivo- lumab. Their patient was treated with intravenous meth- ylprednisolone , which is comparable to our patient. Abbreviations T cell–engaging therapies such as the chimeric antigen BiTe: Bi-specific T cell engagers; CAR T: Chimeric antigen receptor T cells; CRS: Cytokine release syndrome; CTLA-4: Cytotoxic T lymphocyte-associated receptor T (CAR T) cells and bispecific monoclonal antigen-4; HLH: Hemophagocytic lymphohistiocytosis; irAE: Immune-related antibodies / bi-specific T cell engagers (BiTEs) have been adverse event; MAS: Macrophage activation syndrome; PD-1: Programmed promising in the treatment of highly refractory B cell death-1; PDL-1: Programmed death ligand-1 Sadaat and Jang Journal for ImmunoTherapy of Cancer (2018) 6:49 Page 5 of 5 Availability of data and materials 15. Ness KK, Delany JP, Kaste SC, et al. Energy balance and fitness in adult Data sharing is not applicable to this article as no datasets were generated survivors of childhood acute lymphoblastic leukemia Key Points; 2015. or analyzed. https://doi.org/10.1182/blood-2015-01. 16. Tamamyan GN, Kantarjian HM, Ning J, et al. Malignancy-associated hemophagocytic lymphohistiocytosis in adults: relation to Authors’ contributions hemophagocytosis, characteristics, and outcomes. Cancer. 2016; https://doi. Both authors prepared, reviewed and approved the final manuscript. org/10.1002/cncr.30084. 17. Rosado FGN, Kim AS. Hemophagocytic lymphohistiocytosis. Am J Clin Ethics approval and consent to participate Pathol. 2013; https://doi.org/10.1309/AJCP4ZDKJ4ICOUAT. Not applicable. 18. Otrock ZK, Daver N, Eby CS. Diagnostic challenges of Hemophagocytic Lymphohistiocytosis. Clin Lymphoma, Myeloma Leuk. 2017; https://doi.org/ Competing interests 10.1016/j.clml.2017.02.017. The authors declare that they have no competing interests. 19. Wang Y, Wang Z. Treatment of hemophagocytic lymphohistiocytosis. Curr Opin Hematol. 2017; https://doi.org/10.1097/MOH.0000000000000302. 20. Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and therapeutic Publisher’sNote guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. Springer Nature remains neutral with regard to jurisdictional claims in published 2006;48(2):124–31. https://doi.org/10.1002/pbc.21039. maps and institutional affiliations. 21. Hayden A, Park S, Giustini D, Lee AYY, Chen LYC. Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in Author details adults: a systematic scoping review. Blood Rev. 2016;30(6):411–20. https:// Inova Center for Personalized Health, Inova Schar Cancer Institute, 3225 doi.org/10.1016/j.blre.2016.05.001. Gallows Rd, 7th Floor, Tower D, Fairfax, VA 22031, USA. Inova Center for 22. Wang Y, Wang Z, Huang W, et al. Multi-Center Study of DEP Regimen As a Personalized Health, Inova Schar Cancer Institute, 8505 Arlington Blvd Suite Salvage Therapy for Adult Refractory Hemophagocytic Lymphohistiocytosis. 140, Fairfax, VA 22031, USA. Present 56th ASH Annu Meet December 6–9, 2014; San Fr CA Abstr 2748. 2016;126(19):2186–93. https://doi.org/10.3760/cma.j.issn.0253-2727.2014.10.006. Received: 11 December 2017 Accepted: 22 May 2018 23. Shah D, Shrestha R, Ramlal R, Hatton J, Saeed H. Pembrolizumab associated hemophagocytic lymphohistiocytosis. Ann Oncol. 2017;28(6):1403. https:// doi.org/10.1093/annonc/mdx113. References 24. Satzger I, Ivanyi P, Länger F, et al. Treatment-related hemophagocytic 1. Daver N, McClain K, Allen CE, et al. A consensus review on malignancy- lymphohistiocytosis secondary to checkpoint inhibition with nivolumab plus associated hemophagocytic lymphohistiocytosis in adults. Cancer. 2017; ipilimumab; 2018. https://doi.org/10.1016/j.ejca.2018.01.063. https://doi.org/10.1002/cncr.30826. 25. Malissen N, Lacotte J, Du-Thanh A, Gaudy-Marqueste C, Guillot B, Grob JJ. 2. Weitzman S. Approach to Hemophagocytic syndromes. Hematology. 2011; Macrophage activation syndrome: a new complication of checkpoint 2011(1):178–83. https://doi.org/10.1182/asheducation-2011.1.178. inhibitors. Eur J Cancer. 2017; https://doi.org/10.1016/j.ejca.2017.02.016. 3. Ramos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X. 26. Takeshita M, Anai S, Mishima S, Inoue K. Coincidence of immunotherapy- Adult haemophagocytic syndrome. Lancet. 2014;383:1503–16. https://doi. associated hemophagocytic syndrome and rapid tumor regression. Ann org/10.1016/S0140-6736(13)61048-X. Oncol. 2017 https://doi.org/10.1093/annonc/mdw537. 4. Ammann S, Lehmberg K, zur SU, et al. Primary and secondary 27. Zheng PP, Kros JM, Li J. Approved CAR T cell therapies: ice bucket hemophagocytic lymphohistiocytosis have different patterns of T-cell challenges on glaring safety risks and long-term impacts. Drug Discov activation, differentiation and repertoire. Eur J Immunol. 2017;47(2):364–73. Today. 2018. https://doi.org/10.1016/j.drudis.2018.02.012. https://doi.org/10.1002/eji.201646686. 28. Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release 5. Rosado FG, Kim AS. Hemophagocytic lymphohistiocytosis: an update on syndrome associated with novel T cell-engaging therapies. Cancer J (United diagnosis and pathogenesis. Am J Clin Pathol. 2013;139(6):713–27. States). 2014; https://doi.org/10.1097/PPO.0000000000000035. 6. Daver N, Kantarjian H. Malignancy-associated haemophagocytic 29. Saarela M, Senthil K, Jones J, et al. Hemophagocytic lymphohistiocytosis in 2 lymphohistiocytosis in adults. Lancet Oncol. 2017; https://doi.org/10.1016/ patients with multiple sclerosis treated with alemtuzumab. Neurology. 2018; S1470-2045(17)30004-9. https://doi.org/10.1212/WNL.0000000000005420, https://doi.org/10.1212/ 7. Leick MB, Maus MV. Toxicities associated with immunotherapies for WNL.0000000000005420. hematologic malignancies. Best Pract Res Clin Haematol. 2018:1–0. https:// doi.org/10.1016/j.beha.2018.03.004. 8. Champiat S, Lambotte O, Barreau E, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol. 2016;27(4):559–74. https://doi.org/10.1093/annonc/mdv623. 9. Suarez-Almazor ME, Kim ST, Abdel-Wahab N, Diab A. Review: immune- related adverse events with use of checkpoint inhibitors for immunotherapy of Cancer. Arthritis Rheum. 2017; https://doi.org/10.1002/art.40043. 10. 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):2613–20. https://doi.org/10.1002/art.38690. 11. Hejblum G, Lambotte O, Galicier L, et al. A web-based Delphi study for eliciting helpful criteria in the positive diagnosis of hemophagocytic syndrome in adult patients. PLoS One. 2014;9(4) https://doi.org/10.1371/ journal.pone.0094024. 12. Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of Hemophagocytic Lymphohistiocytosis. Pediatr Blood Cancer. 2008; https://doi.org/10.1002/pbc. 13. Grangé S, Buchonnet G, Besnier E, et al. The use of ferritin to identify critically ill patients with secondary Hemophagocytic Lymphohistiocytosis. Crit Care Med. 2016; https://doi.org/10.1097/CCM.0000000000001878. 14. Schaer DJ, Schleiffenbaum B, Kurrer M, et al. Soluble hemoglobin- haptoglobin scavenger receptor CD163 as a lineage-specific marker in the reactive hemophagocytic syndrome. Eur J Haematol. 2005; https://doi.org/ 10.1111/j.1600-0609.2004.00318.x.
Journal for ImmunoTherapy of Cancer – Springer Journals
Published: Jun 5, 2018
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.
All for just $49/month
Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly
Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.
Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.
Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.
All the latest content is available, no embargo periods.
“Hi guys, I cannot tell you how much I love this resource. Incredible. I really believe you've hit the nail on the head with this site in regards to solving the research-purchase issue.”Daniel C.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud
“I must say, @deepdyve is a fabulous solution to the independent researcher's problem of #access to #information.”@deepthiw
“My last article couldn't be possible without the platform @deepdyve that makes journal papers cheaper.”@JoseServera