Hemophagocytic lymphohistiocytosis

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3 regimens on this page
3 variants on this page


Untreated

HLH-94

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Regimen

Study Evidence
Henter et al. 1997 Non-randomized

Initial therapy

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

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, as follows:

Continuation therapy

  • Dexamethasone (Decadron) 10 mg/m2/day 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 μg/L (not clear from the paper whether this is modified or non-modified)

Continuous for up to 52 weeks

References

  1. 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-94: a treatment protocol for hemophagocytic lymphohistiocytosis. HLH study Group of the Histiocyte Society. Med Pediatr Oncol. 1997 May;28(5):342-7. link to original article does not contain protocol 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 verified protocol 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 verified protocol link to PMC article PubMed

HLH-2004

Source: HLH-2004 for untreated hemophagocytic lymphohistiocytosis (HLH)

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Regimen

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

Initial therapy

  • Start allogeneic stem cell transplant (SCT) donor search
  • Dexamethasone (Decadron) in a tapering schedule as follows:
    • Weeks 1 & 2: dexamethasone 10 mg/m2 (route not specified) once per day
    • Weeks 3 & 4: dexamethasone 5 mg/m2 (route not specified) once per day
    • Weeks 5 & 6: dexamethasone 2.5 mg/m2 (route not specified) once per day
    • Week 7: dexamethasone 1.25 mg/m2 (route not specified) once per day
    • Week 8: "taper then discontinue"
  • Etoposide (Vepesid) as follows:
    • Weeks 1 & 2: etoposide 150 mg/m2 IV twice per week
    • Weeks 3 to 8: etoposide 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. Then, titrate 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.
  • 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) IT once per week. Methotrexate doses by age:
      • less than 1 year old: 6 mg each dose
      • 1 to 2 years old: 8 mg each dose
      • 2 to 3 years old: 10 mg each dose
      • greater than 3 years old: 12 mg each dose
    • Weeks 3 to 6: Prednisolone IT once per week. Prednisolone doses by age:
      • less than 1 year old: 4 mg each dose
      • 1 to 2 years old: 6 mg each dose
      • 2 to 3 years old: 8 mg each dose
      • greater than 3 years old: 10 mg each dose

Supportive medications

  • Prophylactic cotrimoxazole (5 mg/kg of trimethoprim equivalent), three times weekly, start on week 1 and treat onwards
  • An oral antimycotic from weeks 1 to 9
  • IvIG 0.5 g/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, as follows:

Continuation 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. 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 full article at ResearchGate link to original article contains verified protocol link to study protocol PubMed

Relapsed or refractory

DEP

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DEP: Doxil (Liposomal doxorubicin), Etoposide, MethylPrednisolone

Regimen

Study Evidence ORR
Wang et al. 2015 Phase II 76%

Note: Liposomal doxorubicin could be repeated, although details are scant in the text. End of etoposide is also somewhat unclear.

Chemotherapy

  • Doxorubicin liposomal (Doxil) 25 mg/m2 IV once on day 1
  • Etoposide (Vepesid) 100 mg/m2 IV once per week
  • 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

One 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 verified protocol link to PMC article PubMed