Treatment Protocol for Hemophagocytic Lymphohistiocytosis 2004

Azienda Ospedaliero, Universitaria Meyer, Leiden University Medical Center, Children's Hospital Medical Center, Cincinnati, Ehime University Graduate School of Medicine, Universitätsklinikum Hamburg-Eppendorf, Baylor College of Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, St. Anna Kinderkrebsforschung, Hospital de Cruces, Hospital JP Garrahan

Without therapy HLH is often fatal, and often rapidly fatal. The treatment protocol HLH-94 has improved survival markedly as compared to the survival earlier. We now aim to improve survival further.

The most dangerous period after HLH diagnosis is the first 2 months. In HLH-2004 we provide additional therapy during this period as compared to in HLH-94.

As compared to the HLH-94 treatment, the main changes are that Cyclosporin A is administered from day 1 and Intrathecal steroids are added to the intrathecal methotrexate. Drugs, dosage, frequency and duration are described in the paragraph "Interventions" below.

10 mg/m2 daily wk 1-2 5 mg/m2 daily wk 3-4 2.5 mg/m2 daily wk 5-6 1.25 mg/m2 daily wk 7 Steroids tapered wk 8 If continuation: Pulses every 2nd wk, 10 mg/m2 for 3 days

150 mg/m2 iv twice/wk (wk 1-2) 150 mg/m2 iv once/wk (wk 3-8) If continuation: 150 mg/m2 iv, every 2nd wk

WK 1-8: - Aim at around 200 microgram/L (trough value). Start: 6 mg/kg daily (divided in 2 daily doses) wk 1, if kidney function is normal. If continuation: - Aim for around 200 microgram/L. Monitor GFR.

If at 2 wks there are progressive neurological symptoms or if an abnormal CSF (cell count and protein) has not improved, then give 4 wkly intrathecal inj. Be aware that some pat may have increased intracranial pressure. Methotrexate: <1 yr 6 mg, 1-2 yrs 8 mg, 2-3 yrs 10 mg, >3 yrs 12 mg. Prednisolone: <1 yr 4 mg, 1-2 yrs 6 mg, 2-3 yrs 8 mg, >3 yrs 10 mg.

Inclusion Criteria: Patients who fulfil the diagnostic criteria of HLH. Exclusion Criteria: Prior cytotoxic or cyclosporin treatment for HLH.

Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007 Feb;48(2):124-31. doi: 10.1002/pbc.21039.

Bergsten E, Horne A, Arico M, Astigarraga I, Egeler RM, Filipovich AH, Ishii E, Janka G, Ladisch S, Lehmberg K, McClain KL, Minkov M, Montgomery S, Nanduri V, Rosso D, Henter JI. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017 Dec 21;130(25):2728-2738. doi: 10.1182/blood-2017-06-788349. Epub 2017 Sep 21.

Bergsten E, Horne A, Hed Myrberg I, Arico M, Astigarraga I, Ishii E, Janka G, Ladisch S, Lehmberg K, McClain KL, Minkov M, Nanduri V, Rosso DA, Sieni E, Winiarski J, Henter JI. Stem cell transplantation for children with hemophagocytic lymphohistiocytosis: results from the HLH-2004 study. Blood Adv. 2020 Aug 11;4(15):3754-3766. doi: 10.1182/bloodadvances.2020002101.