Hemophagocytic lymphohistiocytosis: review of etiologies and management

George, Melissa R

Hemophagocytic lymphohistiocytosis under the age of 16 years. HLH-94 included 8 weeks of initial chemotherapy and immunotherapy, attempting to achieve complete remission, followed by continuation therapy until an acceptable bone marrow donor could be found. The first 8 weeks consisted of dexamethasone at a starting dosage of 10 mg/m 2 body surface area, then tapering down by half in 2-week increments for 6 weeks, then 1 week of 1.25 mg/m 2 , and a subsequent week of taper. Concurrently with the dexamethasone taper, VP-16 therapy was initiated twice weekly during the first 2 weeks, then weekly. After week 8, CSA therapy began and extended for the duration of therapy. Intrathecal methotrexate was included in selected patients with evidence of central nervous system (CNS) involvement. After 8 weeks, pulses of dexamethasone were given at regular intervals. HSCT was recommended for all children with a suitable allogeneic donor. Supportive care may have included an intensive care unit stay, broad-spectrum antibiotics until appropriate culture results were available, microbiological surveillance, HLA testing of patient and family in anticipation of HSCT, and prophylactic antifungals. 7 Conditioning regimens prior to HSCT included busulfan, cyclophosphamide, etoposide, and if the donor was unrelated, antithymocyte globulin (ATG). 244 Retrospective reviews of the HLH-94 treatment protocol morbidity and mortality for 249 patients with longterm follow-up revealed that overall survival and response to therapy did not differ in patients with versus without family history. Overall survival rates were 54%. In this study, 114 (46%) died, and 72 did not receive transplant. Of patient deaths, 64 (89%) occurred in the first year. Of the eight deaths occurring after 1 year of therapy, two had progressive disease without an available HSCT donor, one could not be transplanted due to severe neurological disease, and five relapsed. Overall, HLH-94 achieved complete remission or allowed survival to HSCT in 71% of patients. 244 Given the success of the HLH-94 protocol, in 2004, a revised protocol called HLH-2004 was proposed, which aimed to 1) evaluate a revised initial and continuation therapy with an end goal of HSCT, 2) evaluate and improve results of HSCT with various types of donors, 3) evaluate the prognostic importance of state of remission at the time of HSCT, 4) evaluate long-term neurologic sequelae, and 5) improve understanding of the pathophysiology of HLH by including genotype-phenotype studies and evaluate the prognostic value of NK-cell activity subtyping. HLH-2004 essentially took HLH-94 and moved cyclosporine from later in the regimen to an initial therapy, concurrent with dexamethasone and VP-16. Dexamethasone and VP-16 dosing was the same as in HLH-94. Intrathecal methotrexate was still included for select patients with CNS involvement. In general, HLH-2004 approaches all patients with an initial 8 weeks of chemotherapy, and supports the patient until HSCT can be performed in the case of patients with genetically determined disease or persistent non-genetic disease. Cases which resolve or are non-genetic can cease therapy unless relapse occurs, in which case HSCT would be undertaken. Eligibility requirements include children ,18 years old. Separate concurrent studies have been undertaken on patients .18 years old, and those with CHS, GS, or XLPS. 7 The HLH-2004 protocol officially ceased enrolment at the end of 2011. Long-term outcomes are sti