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Salvage Therapy for Refractory Hemophagocytic Lymphohistiocytosis: a Review of the Published Experience

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Salvage Therapy for Refractory Hemophagocytic Lymphohistiocytosis: a Review of the Published Experience Received: 31 August 2016 Revised: 19 September 2016 Accepted: 20 September 2016 DOI: 10.1002/pbc.26308 Pediatric REVIEW Blood & The American Society of Cancer Pediatric Hematology/Oncology Salvage therapy for refractory hemophagocytic lymphohistiocytosis: A review of the published experience Rebecca A. Marsh1 Michael B. Jordan1,2 Julie-An Talano3 Kim E. Nichols4 Ashish Kumar1 Ahmed Naqvi5 Sarah R. Vaiselbuh6 for the Histiocyte Society Salvage Therapy Working Group 1Division of Bone Marrow Transplantation and Immune Deficiency, Abstract Cincinnati Children’s Hospital, Cincinnati, Ohio Hemophagocytic lymphohistioytosis (HLH) is a severe, life-threatening hyperinflammatory disor- 2Division of Immunobiology, Cincinnati der that requires prompt diagnosis and treatment. Approximately, 25–50% of patients with HLH Children’s Hospital, Cincinnati, Ohio fail to achieve remission with established regimens that include dexamethasone and etoposide, or 3 Division of Pediatric Hematology and Oncology methylprednisolone and antithymocyte globulin (ATG). Some of these patients may require sal- Medical College of Wisconsin, Milwaukee, vage or alternative therapeutic approaches. There is a paucity of literature regarding effective Wisconsin salvage therapies for patients with refractory HLH. In this review, we summarize the published 4Division of Cancer Predisposition, St. Jude Children’s Research Hospital, Memphis, experience of four therapeutics reported for using at least two patients with HLH refractory to Tennessee dexamethasone and etoposide or methylprednisolone and ATG. 5Division of Haematology/Oncology, Department of Pediatrics, The Hospital for KEYWORDS Sick Children, Toronto, Ontario hemophagocytic lymphohistiocytosis, HLH, refractory HLH, salvage therapy 6Children’s Cancer Center, Staten Island University Hospital at Northwell Health, Staten Island, New York Correspondence Rebecca A. Marsh, Division of Bone Mar- row Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229. Email: [email protected] 1 INTRODUCTION lymphocyte granule-mediated cytotoxicity,2–7 although X-linked lymphoproliferative disease type 1 (XLP1 because of mutations in Hemophagocytic lymphohistiocytosis (HLH) is a severe, life- SH2D1A) and XLP type 2 (XLP2 because of mutations in BIRC4)are threatening hyperinflammatory clinical syndrome classically charac- associated with alternative mechanisms of disease.8–11 Other primary terized by fevers, cytopenias, and hepatosplenomegaly. Additionally, immune deficiencies can also be associated with the development some patients may develop other clinical manifestations such as of HLH.12 Outside these known genetic disorders, patients may hepatitis, liver dysfunction, and central nervous system involvement.1 develop HLH that is due to an as-of-yet undiscovered genetic defect, Several typical laboratory manifestations are often observed including and be presumed to have primary HLH due to family history or the elevated ferritin, soluble IL2R, and triglyceride levels, and low levels of recurrence of disease over time. Many patients lack an obvious genetic fibrinogen. etiology for HLH predisposition, and develop what is referred to Genetic diseases that primarily manifest with the development of as “secondary HLH.” Secondary HLH is thought to be triggered in HLH are often grouped together as “primary HLH” (Table 1). Most of normal individuals by severe infections or malignancies, or to occur these diseases are caused by mutations in genes that cripple cytotoxic in patients with immune compromise due to immunosuppressive treatment or underlying autoimmune diseases such as systemic onset juvenile idiopathic arthritis (where HLH is commonly referred to as Abbreviations: ATG, antithymocyte globulin; DEP, doxorubicin, etoposide, and methylprednisolone; HCT, hematopoietic cell transplantation; HLH, hemophagocytic macrophage activation syndrome [MAS]). Regardless of HLH etiology, lymphohistiocytosis; MAS, macrophage activation syndrome Pediatr Blood Cancer 2016; 0:1–7 wileyonlinelibrary.com/journal/pbc c 2016 Wiley Periodicals, Inc. 1 2 MARSH ET AL. TABLE 1 Genetic causes of primary HLH Gene Protein Disease PRF1 Perforin Familial lymphohistiocytosis type 2 UNC13D Munc13-4 Familial lymphohistiocytosis type 3 STX11 Syntaxin-11 Familial lymphohistiocytosis type 4 STXBP2 Syntaxin-binding protein 2 Familial lymphohistiocytosis type 5 RAB27A Ras-related protein Rab-27A Griscelli syndrome type 2 LYST Lysosomal trafficking regulator Chediak-Higashi syndrome SH2D1A Signaling lymphocytic activation molecule (SLAM) associated protein (SAP) X-linked lymphoproliferative syndrome type 1 BIRC4 X-linked inhibitor of apoptosis (XIAP) X-linked lymphoproliferative syndrome type 2 TABLE 2 Established treatment strategies for HLH and success Died and not Relapses Primary treatment included in response following regimen Reference N CR PR NR assessment CR HLH-1994 Henter et al. 113 56 (53%) 34 (32%) 4 (4%) 12 (11%) 7 ATG (rabbit), MP Mahlaoui et al. 38 33 (73%) 11 (24%) 1(2%) 8 (45 courses) CR, complete response; PR, partial response; NR, no response; ATG, antithymocyte globulin; MP, methylprednisolone. HLH is life-threatening and patients require prompt diagnosis and very definition of refractory disease is itself challenging, given that treatment to prevent death. patients with familial HLH can be expected to experience frequent HLH is traditionally managed by one of two established immuno- reactivations, as therapies are weaned. In order to address these chal- suppressive therapeutic regimens that contain corticosteroids with lenges, a Salvage Therapy Working Group was formed within the His- either etoposide or antithymocyte globulin (ATG) (Table 2).13,14 Dex- tiocyte Society to review the published experience with salvage ther- amethasone and etoposide were combined in a prospective trial ini- apies for patients with relapsed or refractory HLH. A summary of the tiated by the Histiocyte Society in 1994 (HLH-1994).13 Cyclosporine data is presented in this paper. was added during the continuation phase of treatment. In an interim report including 113 patients, after 2 months of therapy resolution of 2 METHODS HLH was observed in 53% of patients (some of whom had had a reac- tivation), improvement was observed in an additional 32%, while no improvement was observed in 4% of the patients. Of the patients who 2.1 Literature review died during the entire initial and continuation therapy (n = 25), 20 were Members of the working group reviewed the literature via PubMed related to disease and 4 to toxicity. search strategies. Search terms included HLH or MAS and therapy, An immunotherapeutic approach for HLH that lacked chemother- treatment, salvage, or specific treatment agent names including alem- apy was pioneered in France, which combined ATG (rabbit) and tuzumab, tocilizumab, etanercept, infliximab, adalimumab, rituximab, 14 methylprednisolone. Cyclosporine was also added in the mainte- anakinra, canakinumab, daclizumab, basiliximab, ATG, tacrolimus, nance phase. With this approach, 73% of patients achieved a complete sirolimus, cyclosporine, and doxorubicin. Articles were reviewed if response, but 24% of patients achieved only a partial response and written in English and if published in the year 2000 or later. Articles 2% failed to respond. Notably, of the eight patients, who showed clin- referenced in the reviewed articles were also examined. We included ical remission following the first course of ATG but did not proceed to articles in this review, if the agent(s) used was(were) given to at least allogeneic hematopoietic cell transplantation (HCT), all experienced a two patients who were previously treated with the established ther- relapse of HLH. apies of either steroids and etoposide, or steroids and ATG. Patients Based on the above results, it is clear that approximately 25–50% may have continued on previous therapeutic agents while receiving of patients will fail to achieve a complete response to standard-of- salvage therapy. Patients with primary and secondary forms of HLH care therapy and may require additional treatment with the same were included except for patients with malignancy-associated HLH, drugs or alternative “salvage” agents. Additionally, patients who who were excluded. respond to therapy initially may experience a relapse of HLH. Relapses may respond to intensification of standard-of-care therapy,13,14 or may 2.2 Assessment of refractory disease require additional or alternative therapies. Currently, there is limited literature concerning the salvage ther- The definition of refractory HLH is difficult, and no standard definition apy of patients with resistant or recalcitrant disease, and there are has been widely accepted. Refractory HLH can be considered as failing no consensus guidelines regarding treatment options. Additionally, the to experience an adequate response to conventional therapy,15 though MARSH ET AL. 3 this can be widely interpreted. Some authors have defined refractory 3.2.2 ATG (rabbit) HLH to be the failure to achieve at least a partial response 2 weeks Within the original French report of rabbit ATG (Genzyme) as treat- following standard HLH therapy.16 For the purpose of this review, we ment for familial HLH (Mahlaoui et al.14), two patients received ATG as accepted that patients were considered to have refractory disease as second-line therapy following steroids and etoposide (Table 4). Their reported by the authors. results were reported together
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