Difference between revisions of "Hemophagocytic lymphohistiocytosis"
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− | + | <span id="BackToTop"></span> | |
− | + | <div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px"> | |
− | + | [[#top|Back to Top]] | |
− | + | </div> | |
− | + | {{#lst:Editorial board transclusions|hist}} | |
− | + | *''We have moved [[How I Treat]] articles to a dedicated page.'' | |
− | |||
{| class="wikitable" style="float:right; margin-right: 5px;" | {| class="wikitable" style="float:right; margin-right: 5px;" | ||
|- | |- | ||
− | |<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] | + | |<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div> |
− | <div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] | + | <div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div> |
|} | |} | ||
{{TOC limit|limit=3}} | {{TOC limit|limit=3}} | ||
− | + | =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. [https://doi.org/10.1182/blood.2018894618 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30992265/ PubMed] | ||
=Untreated= | =Untreated= | ||
− | |||
==HLH-94 regimen {{#subobject:a8b7d0|Regimen=1}}== | ==HLH-94 regimen {{#subobject:a8b7d0|Regimen=1}}== | ||
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#c8a2c8"> |
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | + | |[https://doi.org/10.1002/(sici)1096-911x(199705)28:5%3C342::aid-mpo3%3E3.0.co;2-h Henter et al. 1997 (HLH-94)] | |
− | + | |1995-01 to NR | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |[https:// | ||
|style="background-color:#91cf61"|Non-randomized | |style="background-color:#91cf61"|Non-randomized | ||
|- | |- | ||
|} | |} | ||
− | ====Immunosuppressive therapy | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Induction {{#subobject:#131cfd|Variant=1}}=== | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Immunosuppressive therapy==== | ||
*[[Dexamethasone (Decadron)]] in a tapering schedule as follows: | *[[Dexamethasone (Decadron)]] in a tapering schedule as follows: | ||
− | **10 mg/m<sup>2</sup>/day (single or split doses not specified) | + | **Weeks 1 & 2: 10 mg/m<sup>2</sup>/day (single or split doses not specified) |
− | **5 mg/m<sup>2</sup>/day (single or split doses not specified) | + | **Weeks 3 & 4: 5 mg/m<sup>2</sup>/day (single or split doses not specified) |
− | **2.5 mg/m<sup>2</sup>/day (single or split doses not specified) | + | **Weeks 5 & 6: 2.5 mg/m<sup>2</sup>/day (single or split doses not specified) |
− | **1.25 mg/m<sup>2</sup>/day (single or split doses not specified) | + | **Week 7: 1.25 mg/m<sup>2</sup>/day (single or split doses not specified) |
**Taper off during week 8 (exact schedule not specified) | **Taper off during week 8 (exact schedule not specified) | ||
− | *[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV | + | *[[Etoposide (Vepesid)]] as follows: |
− | + | **Weeks 1 & 2: 150 mg/m<sup>2</sup> IV twice per week | |
− | ** | + | **Weeks 3 to 8: 150 mg/m<sup>2</sup> 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. | *[[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==== | |
− | ====Supportive | + | *Prophylactic [[Trimethoprim-Sulfamethoxazole_(Bactrim_DS)|cotrimoxazole]] (5 mg/kg of trimethoprim equivalent), three times weekly |
− | *Prophylactic [[Trimethoprim | ||
*An oral [[:Category:Antifungals|antimycotic]] during initial [[Dexamethasone (Decadron)|dexamethasone]] phase | *An oral [[:Category:Antifungals|antimycotic]] during initial [[Dexamethasone (Decadron)|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:''' | |
− | '''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 | + | </div></div><br> |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | ====Immunosuppressive therapy | + | ===Continuation {{#subobject:#131cfd|Variant=1}}=== |
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Immunosuppressive therapy==== | ||
*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup>/day PO for three days, every two weeks (even weeks) | *[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup>/day PO for three days, every two weeks (even weeks) | ||
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once every two weeks (odd weeks) | *[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once every two weeks (odd weeks) | ||
− | *[[ | + | *[[Cyclosporine|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''' | |
− | ''' | + | </div></div></div> |
− | |||
===References=== | ===References=== | ||
− | # '''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. [https:// | + | # '''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. [https://doi.org/10.1002/(sici)1096-911x(199705)28:5%3C342::aid-mpo3%3E3.0.co;2-h link to original article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/9121398/ PubMed] |
− | ## '''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. [ | + | ## '''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. [https://doi.org/10.1182/blood-2002-01-0172 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/12239144/ PubMed] |
− | ## '''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. [ | + | ## '''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. [https://doi.org/10.1182/blood-2011-06-356261 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208276/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21900192/ PubMed] |
==HLH-2004 regimen {{#subobject:cd0245|Regimen=1}}== | ==HLH-2004 regimen {{#subobject:cd0245|Regimen=1}}== | ||
− | {{#subobject:#bd882d|Variant=1}} | + | <div class="toccolours" style="background-color:#c8a2c8"> |
− | {{:HLH-2004 for | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1002/pbc.21039 Henter et al. 2007 (HLH-2004)] | ||
+ | |Not reported | ||
+ | |style="background-color:#91cf61"|Non-randomized | ||
+ | |- | ||
+ | |} | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Induction {{#subobject:#bd882d|Variant=1}}=== | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Immunosuppressive therapy==== | ||
+ | *Start allogeneic stem cell transplant (SCT) donor search | ||
+ | *[[Dexamethasone (Decadron)]] in a tapering schedule as follows: | ||
+ | **Weeks 1 & 2: 10 mg/m<sup>2</sup> (route not specified) once per day | ||
+ | **Weeks 3 & 4: 5 mg/m<sup>2</sup> (route not specified) once per day | ||
+ | **Weeks 5 & 6: 2.5 mg/m<sup>2</sup> (route not specified) once per day | ||
+ | **Week 7: 1.25 mg/m<sup>2</sup> (route not specified) once per day | ||
+ | **Week 8: "taper then discontinue" | ||
+ | *[[Etoposide (Vepesid)]] as follows: | ||
+ | **Weeks 1 & 2: 150 mg/m<sup>2</sup> IV twice per week | ||
+ | **Weeks 3 to 8: 150 mg/m<sup>2</sup> IV once per week | ||
+ | *[[Cyclosporine|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 (Millipred)|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 [[Trimethoprim-Sulfamethoxazole_(Bactrim_DS)|cotrimoxazole]] (5 mg/kg of trimethoprim equivalent) PO three times per week, starting on week 1 | ||
+ | *An oral [[:Category:Antifungals|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:''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#fff2ae"> | ||
+ | ====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. | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Continuation {{#subobject:#131cfd|Variant=1}}=== | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Immunosuppressive therapy==== | ||
+ | ''Starts during week 9.'' | ||
+ | *[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup> (route not specified) once per day for three days, every two weeks (on even weeks) | ||
+ | *[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once every two weeks (on odd weeks) | ||
+ | *[[Cyclosporine|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''' | ||
+ | </div></div></div> | ||
+ | ===References=== | ||
+ | #'''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. [https://doi.org/10.1002/pbc.21039 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.researchgate.net/file.PostFileLoader.html?id=557ab7b36307d92f338b457a&assetKey=AS%3A273796236283904%401442289517969 link to study protocol] [https://pubmed.ncbi.nlm.nih.gov/16937360/ PubMed] | ||
+ | ## '''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. [https://doi.org/10.1182/blood-2017-06-788349 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5785801/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28935695/ PubMed] | ||
=Relapsed or refractory= | =Relapsed or refractory= | ||
− | |||
==DEP {{#subobject:53c1bc|Regimen=1}}== | ==DEP {{#subobject:53c1bc|Regimen=1}}== | ||
− | + | DEP: '''<u>D</u>'''oxil (Pegylated liposomal doxorubicin), '''<u>E</u>'''toposide, Methyl'''<u>P</u>'''rednisolone | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | DEP: '''<u>D</u>'''oxil ( | ||
− | |||
===Regimen {{#subobject:#c43103|Variant=1}}=== | ===Regimen {{#subobject:#c43103|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 80%; text-align:center;" |
− | !style="width: | + | !style="width: 25%"|Study |
− | !style="width: | + | !style="width: 25%"|Dates of enrollment |
− | !style="width: | + | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] |
+ | !style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]] | ||
|- | |- | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635114/ Wang et al. 2015a] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635114/ Wang et al. 2015a] | ||
− | |style="background-color:#91cf61"|Phase | + | |2013-06 to 2014-06 |
− | |76% | + | |style="background-color:#91cf61"|Phase 2 |
+ | |ORR: 76% | ||
|- | |- | ||
|} | |} | ||
− | ''Note: | + | ''Note: Pegylated liposomal doxorubicin could be repeated, although details are scant in the text.'' |
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Pegylated liposomal doxorubicin (Doxil)]] 25 mg/m<sup>2</sup> IV once on day 1 | *[[Pegylated liposomal doxorubicin (Doxil)]] 25 mg/m<sup>2</sup> IV once on day 1 | ||
− | *[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per | + | *[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22 |
+ | ====Glucocorticoid therapy==== | ||
*[[Methylprednisolone (Solumedrol)]] as follows: | *[[Methylprednisolone (Solumedrol)]] as follows: | ||
**Days 1 to 3: 15 mg/kg/day | **Days 1 to 3: 15 mg/kg/day | ||
Line 97: | Line 164: | ||
**Days 36 to 42: 0.2 mg/kg/day | **Days 36 to 42: 0.2 mg/kg/day | ||
**Days 43 to 49: 0.1 mg/kg/day | **Days 43 to 49: 0.1 mg/kg/day | ||
− | + | '''7-week course''' | |
− | ''' | + | </div></div> |
− | + | ===References=== | |
+ | # 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. [https://doi.org/10.1182/blood-2015-05-644914 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635114/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26289641/ PubMed] ChiCTR-IPC-14005514 | ||
+ | ==Emapalumab & Dexamethasone {{#subobject:aadbd0|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:#13kvbmd|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1056/nejmoa1911326 Locatelli et al. 2020 (NI-0501-04)] | ||
+ | |Not reported | ||
+ | |style="background-color:#91cf61"|Non-randomized Phase 2/3 (RT) | ||
+ | |- | ||
+ | |[https://doi.org/10.1056/nejmoa1911326 Locatelli et al. 2020 (NI-0501-05)] | ||
+ | |Not reported | ||
+ | |style="background-color:#91cf61"|Phase 2/3 | ||
+ | |- | ||
+ | |} | ||
+ | ''Note: some untreated patients were included in the trials; however, the FDA approval is for relapsed/refractory disease.'' | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Immunosuppressive therapy==== | ||
+ | *[[Emapalumab (Gamifant)]] | ||
+ | *[[Dexamethasone (Decadron)]] | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # | + | # '''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. [https://doi.org/10.1056/nejmoa1911326 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32374962/ PubMed] [https://clinicaltrials.gov/study/NCT01818492 NCT01818492] |
− | + | # '''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. [https://doi.org/10.1056/nejmoa1911326 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32374962/ PubMed] [https://clinicaltrials.gov/study/NCT02069899 NCT02069899] | |
[[Category:Hemophagocytic lymphohistiocytosis regimens]] | [[Category:Hemophagocytic lymphohistiocytosis regimens]] | ||
[[Category:Disease-specific pages]] | [[Category:Disease-specific pages]] | ||
[[Category:Histiocytoses]] | [[Category:Histiocytoses]] |
Latest revision as of 12:21, 15 July 2024
Section editor | |
---|---|
Gaurav Goyal, MD UAB Birmingham, AL, USA |
- 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 | Dates of enrollment | Evidence |
---|---|---|
Henter et al. 1997 (HLH-94) | 1995-01 to NR | 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
- 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
- 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 dosing details in manuscript have been reviewed by our editors PubMed
- 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed
HLH-2004 regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Henter et al. 2007 (HLH-2004) | Not reported | 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
- 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 dosing details in manuscript have been reviewed by our editors link to study protocol PubMed
- 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 | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Wang et al. 2015a | 2013-06 to 2014-06 | 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
- 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed ChiCTR-IPC-14005514
Emapalumab & Dexamethasone
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Locatelli et al. 2020 (NI-0501-04) | Not reported | Non-randomized Phase 2/3 (RT) |
Locatelli et al. 2020 (NI-0501-05) | Not reported | Phase 2/3 |
Note: some untreated patients were included in the trials; however, the FDA approval is for relapsed/refractory disease.
Immunosuppressive therapy
References
- 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
- 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