Difference between revisions of "Erdheim-Chester disease"

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m (Jwarner moved page Histiocytoses to Erdheim-Chester disease: Disambiguation)
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=Erdheim-Chester disease (ECD)=
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=Guidelines=
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*[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110656/ Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease (2014)] [https://www.ncbi.nlm.nih.gov/pubmed/24850756 PubMed]
  
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==Guidelines==
+
=All lines of therapy=
−
*[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110656/ Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease (2014)] [https://www.ncbi.nlm.nih.gov/pubmed/24850756 PubMed]
 
  
 
==Sirolimus & Prednisone {{#subobject:a5e5cc|Regimen=1}}==
 
==Sirolimus & Prednisone {{#subobject:a5e5cc|Regimen=1}}==
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# Haroche J, Cohen-Aubart F, Emile JF, Maksud P, Drier A, Tolédano D, Barete S, Charlotte F, Cluzel P, Donadieu J, Benameur N, Grenier PA, Besnard S, Ory JP, Lifermann F, Idbaih A, Granel B, Graffin B, Hervier B, Arnaud L, Amoura Z. Reproducible and sustained efficacy of targeted therapy with vemurafenib in patients with BRAFV600E-mutated Erdheim-Chester disease. J Clin Oncol. 2015 Feb 10;33(5):411-8. Epub 2014 Nov 24. [http://jco.ascopubs.org/content/33/5/411.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25422482 PubMed]
 
# Haroche J, Cohen-Aubart F, Emile JF, Maksud P, Drier A, Tolédano D, Barete S, Charlotte F, Cluzel P, Donadieu J, Benameur N, Grenier PA, Besnard S, Ory JP, Lifermann F, Idbaih A, Granel B, Graffin B, Hervier B, Arnaud L, Amoura Z. Reproducible and sustained efficacy of targeted therapy with vemurafenib in patients with BRAFV600E-mutated Erdheim-Chester disease. J Clin Oncol. 2015 Feb 10;33(5):411-8. Epub 2014 Nov 24. [http://jco.ascopubs.org/content/33/5/411.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25422482 PubMed]
 
# Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, Wolf J, Raje NS, Diamond EL, Hollebecque A, Gervais R, Elez-Fernandez ME, Italiano A, Hofheinz RD, Hidalgo M, Chan E, Schuler M, Lasserre SF, Makrutzki M, Sirzen F, Veronese ML, Tabernero J, Baselga J. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015 Aug 20;373(8):726-736. [http://www.nejm.org/doi/full/10.1056/NEJMoa1502309 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971773/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26287849 PubMed]
 
# Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, Wolf J, Raje NS, Diamond EL, Hollebecque A, Gervais R, Elez-Fernandez ME, Italiano A, Hofheinz RD, Hidalgo M, Chan E, Schuler M, Lasserre SF, Makrutzki M, Sirzen F, Veronese ML, Tabernero J, Baselga J. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015 Aug 20;373(8):726-736. [http://www.nejm.org/doi/full/10.1056/NEJMoa1502309 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971773/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26287849 PubMed]
−
 
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=Langerhans cell histiocytosis (LCH)=
 
−
 
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==Cladribine monotherapy {{#subobject:da32fb|Regimen=1}}==
 
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{| class="wikitable" style="float:right; margin-left: 5px;"
 
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|-
 
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|[[#top|back to top]]
 
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|}
 
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===Regimen {{#subobject:1ef1c0|Variant=1}}===
 
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{| border="1" style="text-align:center;" !align="left"
 
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|'''Study'''
 
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|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|-
 
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|[http://onlinelibrary.wiley.com/doi/10.1002/pbc.22229/abstract Weitzman et al. 2009 (LCH-S-98)]
 
−
|style="background-color:#EEEE00"|Phase II
 
−
|-
 
−
|}
 
−
To be completed
 
−
====Chemotherapy====
 
−
*[[Cladribine (Leustatin)]]
 
−
 
−
===References===
 
−
# Weitzman S, Braier J, Donadieu J, Egeler RM, Grois N, Ladisch S, Pötschger U, Webb D, Whitlock J, Arceci RJ. 2'-Chlorodeoxyadenosine (2-CdA) as salvage therapy for Langerhans cell histiocytosis (LCH). results of the LCH-S-98 protocol of the Histiocyte Society. Pediatr Blood Cancer. 2009 Dec 15;53(7):1271-6. [http://onlinelibrary.wiley.com/doi/10.1002/pbc.22229/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19731321 PubMed]
 
−
 
−
==Cladribine & Cytarabine {{#subobject:4c5b41|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
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|-
 
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|[[#top|back to top]]
 
−
|}
 
−
 
−
===Regimen {{#subobject:7b85e8|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624454/ Donadieu et al. 2015]
 
−
|style="background-color:#EEEE00"|Phase II
 
−
|-
 
−
|}
 
−
====Chemotherapy, induction====
 
−
*[[Cladribine (Leustatin)]] 9 mg/m<sup>2</sup> IV over 2 hours once per day on days 2 to 6, '''should not be administered simultaneously with cytarabine'''
 
−
**Children weighing less than 10 kg received a dose of 0.3 mg/kg/day
 
−
*[[Cytarabine (Cytosar)]] 500 mg/m<sup>2</sup> IV over 2 hours twice per day on days 1 to 5, '''should not be administered simultaneously with cladribine'''
 
−
 
−
'''35-day cycle for 2 or more cycles'''
 
−
 
−
''Patients with a "good response" proceeded to consolidation therapy:''
 
−
 
−
====Chemotherapy, consolidation====
 
−
*[[Cladribine (Leustatin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
 
−
'''21-day cycle for 2 cycles, followed by:'''
 
−
 
−
====Chemotherapy, maintenance====
 
−
*[[Vinblastine (Velban)]] 6 mg/m<sup>2</sup> IV once every 2 weeks for 6 months
 
−
*[[Prednisolone (Millipred)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 5 of every 2nd week for 6 months
 
−
*[[Mercaptopurine (Purinethol)]] 50 mg/m<sup>2</sup> PO once per day for 18 months
 
−
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once per week for 18 months
 
−
 
−
'''Total of 18 months of maintenance'''
 
−
 
−
===References===
 
−
<!-- Preliminary data from this study were presented orally at the 30th meeting of the Histiocyte Society, Washington, DC, 22 October 2013. -->
 
−
# Donadieu J, Bernard F, van Noesel M, Barkaoui M, Bardet O, Mura R, Arico M, Piguet C, Gandemer V, Armari Alla C, Clausen N, Jeziorski E, Lambilliote A, Weitzman S, Henter JI, Van Den Bos C; Salvage Group of the Histiocyte Society. Cladribine and cytarabine in refractory multisystem Langerhans cell histiocytosis: results of an international phase 2 study. Blood. 2015 Sep 17;126(12):1415-23. Epub 2015 Jul 20. [http://www.bloodjournal.org/content/126/12/1415.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624454/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26194764 PubMed]
 
−
 
−
==Etoposide & Prednisone {{#subobject:566a87|Regimen=1}}==
 
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{| class="wikitable" style="float:right; margin-left: 5px;"
 
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|-
 
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|[[#top|back to top]]
 
−
|}
 
−
 
−
===Regimen {{#subobject:#3c6b84|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
−
|[[Levels_of_Evidence#Efficacy|'''Efficacy''']]
 
−
|-
 
−
|[http://www.jpeds.com/article/S0022-3476(01)07325-5/abstract Gadner et al. 2001 (LCH-I)]
 
−
|style="background-color:#00CD00"|Phase III
 
−
|[[Histiocytoses#Vinblastine_.26_Prednisone|Vinblastine & Prednisone]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
To be completed
 
−
====Chemotherapy====
 
−
*[[Etoposide (Vepesid)]]
 
−
*[[Prednisone (Sterapred)]]
 
−
 
−
===References===
 
−
# Gadner H, Grois N, Arico M, Broadbent V, Ceci A, Jakobson A, Komp D, Michaelis J, Nicholson S, Pötschger U, Pritchard J, Ladisch S; Histiocyte Society. A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr. 2001 May;138(5):728-34. Erratum in: J Pediatr 2001 Jul;139(1):170. [http://www.jpeds.com/article/S0022-3476(01)07325-5/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11343051 PubMed]
 
−
 
−
==Etoposide, Vinblastine, Prednisone {{#subobject:5145a8|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
 
−
===Regimen {{#subobject:#7ace0e|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
−
|[[Levels_of_Evidence#Efficacy|'''Efficacy''']]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/111/5/2556.long Gadner et al. 2007 (LCH-II)]
 
−
|style="background-color:#00CD00"|Phase III
 
−
|[[Histiocytoses#Vinblastine_.26_Prednisone|Vinblastine & Prednisone]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''Total duration of therapy is 24 weeks.''
 
−
====Chemotherapy, initial====
 
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV over 1 hour once per week
 
−
*[[Vinblastine (Velban)]] 6 mg/m<sup>2</sup> IV bolus once per week
 
−
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup>/day split TID for 4 weeks, then tapering off over 2 weeks
 
−
 
−
'''6-week course, followed by:'''
 
−
 
−
====Chemotherapy, continuation====
 
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV over 1 hour once on day 1
 
−
*[[Vinblastine (Velban)]] 6 mg/m<sup>2</sup> IV bolus once on day 1
 
−
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup>/day split TID on days 1 to 5
 
−
 
−
'''21-day cycle for 6 cycles'''
 
−
 
−
===References===
 
−
# Gadner H, Grois N, Pötschger U, Minkov M, Aricò M, Braier J, Broadbent V, Donadieu J, Henter JI, McCarter R, Ladisch S; Histiocyte Society. Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood. 2008 Mar 1;111(5):2556-62. Epub 2007 Dec 18. [http://www.bloodjournal.org/content/111/5/2556.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18089850 PubMed]
 
−
 
−
==Methotrexate, Vinblastine, Prednisone {{#subobject:2d772c|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
 
−
===Regimen {{#subobject:#f569ce|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
−
|[[Levels_of_Evidence#Efficacy|'''Efficacy''']]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/121/25/5006.long Gadner et al. 2013 (LCH-III)]
 
−
|style="background-color:#00CD00"|Phase III
 
−
|[[Histiocytoses#Vinblastine_.26_Prednisone|Vinblastine & Prednisone]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
To be completed
 
−
====Chemotherapy====
 
−
*[[Methotrexate (MTX)]]
 
−
*[[Vinblastine (Velban)]]
 
−
*[[Prednisone (Sterapred)]]
 
−
 
−
===References===
 
−
# Gadner H, Minkov M, Grois N, Pötschger U, Thiem E, Aricò M, Astigarraga I, Braier J, Donadieu J, Henter JI, Janka-Schaub G, McClain KL, Weitzman S, Windebank K, Ladisch S; Histiocyte Society. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood. 2013 Jun 20;121(25):5006-14. Epub 2013 Apr 15. [http://www.bloodjournal.org/content/121/25/5006.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23589673 PubMed]
 
−
 
−
==Vemurafenib monotherapy {{#subobject:953978|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
 
−
===Regimen {{#subobject:#73ec1b|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971773/ Hyman et al. 2015]
 
−
|style="background-color:#ff0000"|Phase II, <20 pts in this arm
 
−
|-
 
−
|}
 
−
''This was part of a basket trial, all patients had BRAF V600E mutations.''
 
−
====Chemotherapy====
 
−
*[[Vemurafenib (Zelboraf)]] 960 mg PO BID
 
−
 
−
'''Duration of treatment not specified'''
 
−
 
−
===References===
 
−
# Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, Wolf J, Raje NS, Diamond EL, Hollebecque A, Gervais R, Elez-Fernandez ME, Italiano A, Hofheinz RD, Hidalgo M, Chan E, Schuler M, Lasserre SF, Makrutzki M, Sirzen F, Veronese ML, Tabernero J, Baselga J. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med. 2015 Aug 20;373(8):726-736. [http://www.nejm.org/doi/full/10.1056/NEJMoa1502309 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971773/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26287849 PubMed]
 
−
 
−
==Vinblastine & Prednisone {{#subobject:378322|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
 
−
===Regimen {{#subobject:#bf6a74|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
−
|[[Levels_of_Evidence#Efficacy|'''Efficacy''']]
 
−
|-
 
−
|[http://www.jpeds.com/article/S0022-3476(01)07325-5/abstract Gadner et al. 2001 (LCH-I)]
 
−
|style="background-color:#00CD00"|Phase III
 
−
|[[Histiocytoses#Etoposide_.26_Prednisone|Etoposide & Prednisone]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[http://www.bloodjournal.org/content/111/5/2556.long Gadner et al. 2007 (LCH-II)]
 
−
|style="background-color:#00CD00"|Phase III
 
−
|[[Histiocytoses#Etoposide.2C_Vinblastine.2C_Prednisone|Etoposide, Vinblastine, Prednisone]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|[http://www.bloodjournal.org/content/121/25/5006.long Gadner et al. 2013 (LCH-III)]
 
−
|style="background-color:#00CD00"|Phase III
 
−
|[[Histiocytoses#Methotrexate.2C_Vinblastine.2C_Prednisone|Methotrexate, Vinblastine, Prednisone]]
 
−
|style="background-color:#ffffbf"|Seems not superior
 
−
|-
 
−
|}
 
−
''Total duration of therapy is 24 weeks, in LCH-II.''
 
−
====Chemotherapy, initial====
 
−
*[[Vinblastine (Velban)]] 6 mg/m<sup>2</sup> IV bolus once per week
 
−
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup>/day split TID for 4 weeks, then tapering off over 2 weeks
 
−
 
−
'''6-week course, followed by:'''
 
−
 
−
====Chemotherapy, continuation====
 
−
*[[Vinblastine (Velban)]] 6 mg/m<sup>2</sup> IV bolus once on day 1
 
−
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup>/day split TID on days 1 to 5
 
−
 
−
'''21-day cycle for 6 cycles'''
 
−
 
−
===References===
 
−
# Gadner H, Grois N, Arico M, Broadbent V, Ceci A, Jakobson A, Komp D, Michaelis J, Nicholson S, Pötschger U, Pritchard J, Ladisch S; Histiocyte Society. A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr. 2001 May;138(5):728-34. Erratum in: J Pediatr 2001 Jul;139(1):170. [http://www.jpeds.com/article/S0022-3476(01)07325-5/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11343051 PubMed]
 
−
# Gadner H, Grois N, Pötschger U, Minkov M, Aricò M, Braier J, Broadbent V, Donadieu J, Henter JI, McCarter R, Ladisch S; Histiocyte Society. Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood. 2008 Mar 1;111(5):2556-62. Epub 2007 Dec 18. [http://www.bloodjournal.org/content/111/5/2556.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18089850 PubMed]
 
−
# Gadner H, Minkov M, Grois N, Pötschger U, Thiem E, Aricò M, Astigarraga I, Braier J, Donadieu J, Henter JI, Janka-Schaub G, McClain KL, Weitzman S, Windebank K, Ladisch S; Histiocyte Society. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood. 2013 Jun 20;121(25):5006-14. Epub 2013 Apr 15. [http://www.bloodjournal.org/content/121/25/5006.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23589673 PubMed]
 
  
 
[[Category:Erdheim-Chester disease regimens]]
 
[[Category:Erdheim-Chester disease regimens]]
−
[[Category:Langerhans cell histiocytosis regimens]]
 
 
[[Category:Disease-specific pages]]
 
[[Category:Disease-specific pages]]
−
[[Category:Disease index]]
+
[[Category:Histiocytoses]]

Revision as of 02:43, 14 October 2017

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Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are invited to contribute to the site.

3 regimens on this page
4 variants on this page


Guidelines

All lines of therapy

Sirolimus & Prednisone

back to top

Regimen

Study Evidence
Gianfreda et al. 2015 Pilot, <20 pts in this arm

Chemotherapy

  • Sirolimus (Rapamune) 2 mg PO once per day, titrated to achieve a blood level of 8 to 12 ng/mL
  • Prednisone (Sterapred) as follows:
    • Month 1: 0.75 mg/kg/day PO
    • Month 2: 0.5 mg/k/day PO
    • Months 3 & 4: 0.25 mg/kg/day PO
    • Months 5 & 6: 0.125 mg/kg/day PO
    • Month 7 onwards: tapered to a dose of 2.5 to 5 mg PO once per day

Given for up to 2 years for responders and stable disease, with optional extension beyond 2 years

References

  1. Gianfreda D, Nicastro M, Galetti M, Alberici F, Corradi D, Becchi G, Baldari G, De Filippo M, Ferretti S, Moroni G, Foti R, Di Gangi M, Jeannin G, Saffroy R, Emile JF, Buzio C, Vaglio A. Sirolimus plus prednisone for Erdheim-Chester disease: an open-label trial. Blood. 2015 Sep 3;126(10):1163-71. Epub 2015 Jun 3. link to original article contains verified protocol PubMed

Vemurafenib monotherapy

back to top

Regimen #1

Study Evidence
Hyman et al. 2015 Phase II, <20 pts in this arm

This was part of a basket trial, all patients had BRAF V600E mutations.

Chemotherapy

Duration of treatment not specified

Regimen #2

Study Evidence
Haroche et al. 2014 Pilot, <20 pts

Patients enrolled all had BRAF V600E mutation. This is the dose after de-escalation after the first four patients had excess adverse events.

Chemotherapy

Given until progression of disease or unacceptable toxicity

References

  1. Haroche J, Cohen-Aubart F, Emile JF, Maksud P, Drier A, Tolédano D, Barete S, Charlotte F, Cluzel P, Donadieu J, Benameur N, Grenier PA, Besnard S, Ory JP, Lifermann F, Idbaih A, Granel B, Graffin B, Hervier B, Arnaud L, Amoura Z. Reproducible and sustained efficacy of targeted therapy with vemurafenib in patients with BRAFV600E-mutated Erdheim-Chester disease. J Clin Oncol. 2015 Feb 10;33(5):411-8. Epub 2014 Nov 24. link to original article contains verified protocol PubMed
  2. Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, Wolf J, Raje NS, Diamond EL, Hollebecque A, Gervais R, Elez-Fernandez ME, Italiano A, Hofheinz RD, Hidalgo M, Chan E, Schuler M, Lasserre SF, Makrutzki M, Sirzen F, Veronese ML, Tabernero J, Baselga J. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015 Aug 20;373(8):726-736. link to original article contains protocol link to PMC article PubMed
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