Hemophagocytic lymphohistiocytosis

Section editor
	Gaurav Goyal, MD UAB Birmingham, AL, USA LinkedIn

• We have moved How I Treat articles to a dedicated page.

4 regimens on this page 4 variants on this page

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

Histiocyte Society

• 2019: La Rosée P, Horne A, Hines M, von Bahr Greenwood T, Machowicz R, Berliner N, Birndt S, Gil-Herrera J, Girschikofsky M, Jordan MB, Kumar A, van Laar JA, Lachmann G, Nichols KE, Ramanan AV, Wang Y, Wang Z, Janka G, Henter JI. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019 Jun 6;133(23):2465-2477. Epub 2019 Apr 16. link to original article PubMed

Untreated

HLH-94 regimen

Study	Evidence
Henter et al. 1997 (HLH-94)	Non-randomized

Induction

Immunosuppressive therapy

• Dexamethasone (Decadron) in a tapering schedule as follows:
  • Weeks 1 & 2: 10 mg/m²/day (single or split doses not specified)
  • Weeks 3 & 4: 5 mg/m²/day (single or split doses not specified)
  • Weeks 5 & 6: 2.5 mg/m²/day (single or split doses not specified)
  • Week 7: 1.25 mg/m²/day (single or split doses not specified)
  • Taper off during week 8 (exact schedule not specified)
• Etoposide (Vepesid) as follows:
  • Weeks 1 & 2: 150 mg/m² IV twice per week
  • Weeks 3 to 8: 150 mg/m² IV once per week

CNS therapy

• Methotrexate (MTX) (dose not specified) IT once per week for weeks 3 to 6 in patients with progressive neurological symptoms and/or persisting abnormal cerebrospinal fluid findings.

Supportive therapy

• Prophylactic cotrimoxazole (5 mg/kg of trimethoprim equivalent), three times weekly
• An oral antimycotic during initial dexamethasone phase

8-week course; patients without familial or persistent disease then stopped. Patients with familial, persistent, or relapsed disease were treated with up to one year of continuation therapy, until an allogeneic HCT could be performed:

Continuation

Immunosuppressive therapy

• Dexamethasone (Decadron) 10 mg/m²/day PO for three days, every two weeks (even weeks)
• Etoposide (Vepesid) 150 mg/m² IV once every two weeks (odd weeks)
• Cyclosporine A aiming for trough blood levels of 200 mcg/L (not clear from the paper whether this is modified or non-modified)

Up to 52-week course

References

1. HLH-94: Henter JI, Aricò M, Egeler RM, Elinder G, Favara BE, Filipovich AH, Gadner H, Imashuku S, Janka-Schaub G, Komp D, Ladisch S, Webb D; HLH study Group of the Histiocyte Society. HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. Med Pediatr Oncol. 1997 May;28(5):342-7. link to original article does not contain dosing details PubMed
   1. Update: Henter JI, Samuelsson-Horne A, Aricò M, Egeler RM, Elinder G, Filipovich AH, Gadner H, Imashuku S, Komp D, Ladisch S, Webb D, Janka G; Histocyte Society. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002 Oct 1;100(7):2367-73. link to original article contains dosing details in manuscript PubMed
   2. Update: Trottestam H, Horne A, Aricò M, Egeler RM, Filipovich AH, Gadner H, Imashuku S, Ladisch S, Webb D, Janka G, Henter JI; Histiocyte Society. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011 Oct 27;118(17):4577-84. Epub 2011 Sep 6. link to original article contains dosing details in manuscript link to PMC article PubMed

HLH-2004 regimen

Study	Evidence
Henter et al. 2007 (HLH-2004)	Non-randomized

Induction

Immunosuppressive therapy

• Start allogeneic stem cell transplant (SCT) donor search
• Dexamethasone (Decadron) in a tapering schedule as follows:
  • Weeks 1 & 2: 10 mg/m² (route not specified) once per day
  • Weeks 3 & 4: 5 mg/m² (route not specified) once per day
  • Weeks 5 & 6: 2.5 mg/m² (route not specified) once per day
  • Week 7: 1.25 mg/m² (route not specified) once per day
  • Week 8: "taper then discontinue"
• Etoposide (Vepesid) as follows:
  • Weeks 1 & 2: 150 mg/m² IV twice per week
  • Weeks 3 to 8: 150 mg/m² IV once per week
• Cyclosporine A 3 mg/kg/dose by mouth twice per day (total dose per day is 6 mg/kg), if normal kidney function.

Intrathecal therapy

To "start only if progressive neurological symptoms or if an abnormal CSF has not improved," maximum of 4 doses, as follows:

• Weeks 3 to 6: Methotrexate (MTX) (dosed by age as listed below) , by the following age-based criteria:
  • Younger than 1 year old: 6 mg IT once per week
  • 1 to 2 years old: 8 mg IT once per week
  • 2 to 3 years old: 10 mg IT once per week
  • Older than 3 years old: 12 mg IT once per week
• Weeks 3 to 6: Prednisolone IT once per week, by the following age-based criteria:
  • Younger than 1 year old: 4 mg IT once per week
  • 1 to 2 years old: 6 mg IT once per week
  • 2 to 3 years old: 8 mg IT once per week
  • Older than 3 years old: 10 mg IT once per week

Supportive therapy

• Prophylactic cotrimoxazole (5 mg/kg of trimethoprim equivalent) PO three times per week, starting on week 1
• An oral antimycotic from weeks 1 to 9
• Intravenous immunoglobulin (IVIG) 500 mg/kg IV once every 4 weeks
• "Gastroprotection suggested" for weeks 1 to 9

8-week course; patients with resolved, non-familial, non-genetically verified disease stopped therapy. Patients with familial, genetically verified, persistent, or reactivation/relapsed disease continued to continuation therapy, until an allogeneic HCT could be performed:

Dose and schedule modifications

• Titrate cyclosporine doses with goal of levels around 200 mcg/L (monoclonal, trough level). It was not clear from the paper whether this is modified or non-modified cyclosporine.

Continuation

Immunosuppressive therapy

Starts during week 9.

• Dexamethasone (Decadron) 10 mg/m² (route not specified) once per day for three days, every two weeks (on even weeks)
• Etoposide (Vepesid) 150 mg/m² IV once every two weeks (on odd weeks)
• Cyclosporine A by mouth twice per day, aiming for trough blood levels of 200 mcg/L (not clear from the paper whether this is modified or non-modified)
• Proceed with allogeneic stem cell transplant (SCT) as soon as an acceptable donor is found, such as:
  • HLA-idential record donor
  • Matched unrelated donor
  • Mismatched unrelated donor
  • Family haploidentical donor

Used continuously, with allogeneic stem cell transplant done when possible

References

1. HLH-2004: Henter JI, Horne A, Aricó 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. link to original article contains dosing details in manuscript link to study protocol PubMed
   1. Update: Bergsten E, Horne A, Aricó 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. Epub 2017 Sep 21. link to original article link to PMC article PubMed

Relapsed or refractory

DEP

DEP: Doxil (Pegylated liposomal doxorubicin), Etoposide, MethylPrednisolone

Regimen

Study	Evidence	Efficacy
Wang et al. 2015a	Phase 2	ORR: 76%

Note: Pegylated liposomal doxorubicin could be repeated, although details are scant in the text.

Chemotherapy

• Pegylated liposomal doxorubicin (Doxil) 25 mg/m² IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1, 8, 15, 22

Glucocorticoid therapy

• Methylprednisolone (Solumedrol) as follows:
  • Days 1 to 3: 15 mg/kg/day
  • Days 4 to 6: 2 mg/kg/day
  • Days 7 to 10: 1 mg/kg/day
  • Days 11 to 14: 0.75 mg/kg/day
  • Days 15 to 21: 0.5 mg/kg/day
  • Days 22 to 28: 0.4 mg/kg/day
  • Days 29 to 35: 0.3 mg/kg/day
  • Days 36 to 42: 0.2 mg/kg/day
  • Days 43 to 49: 0.1 mg/kg/day

7-week course

References

1. Wang Y, Huang W, Hu L, Cen X, Li L, Wang J, Shen J, Wei N, Wang Z. Multicenter study of combination DEP regimen as a salvage therapy for adult refractory hemophagocytic lymphohistiocytosis. Blood. 2015 Nov 5;126(19):2186-92. Epub 2015 Aug 19. link to original article contains dosing details in manuscript link to PMC article PubMed ChiCTR-IPC-14005514

Emapalumab & Dexamethasone

Regimen

Study	Evidence
Locatelli et al. 2020 (NI-0501-04)	Non-randomized Phase 2/3 (RT)
Locatelli et al. 2020 (NI-0501-05)	Phase 2/3

Note: some untreated patients were included in the trials; however, the FDA approval is for relapsed/refractory disease.

Immunosuppressive therapy

• Emapalumab (Gamifant)
• Dexamethasone (Decadron)

References

1. NI-0501-04: Locatelli F, Jordan MB, Allen C, Cesaro S, Rizzari C, Rao A, Degar B, Garrington TP, Sevilla J, Putti MC, Fagioli F, Ahlmann M, Dapena Diaz JL, Henry M, De Benedetti F, Grom A, Lapeyre G, Jacqmin P, Ballabio M, de Min C. Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis. N Engl J Med. 2020 May 7;382(19):1811-1822. link to original article PubMed NCT01818492
2. NI-0501-05: Locatelli F, Jordan MB, Allen C, Cesaro S, Rizzari C, Rao A, Degar B, Garrington TP, Sevilla J, Putti MC, Fagioli F, Ahlmann M, Dapena Diaz JL, Henry M, De Benedetti F, Grom A, Lapeyre G, Jacqmin P, Ballabio M, de Min C. Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis. N Engl J Med. 2020 May 7;382(19):1811-1822. link to original article PubMed NCT02069899