Difference between revisions of "Langerhans cell histiocytosis"

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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 [[How_to_contribute|invited to contribute to the site]].
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{{#lst:Editorial board transclusions|hist}}
 
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|<div style="background-color: #66FF66; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} regimens on this page</b></font></div>
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''Note: the majority of the regimens on this page are intended for multi-system Langerhans cell histiocytosis (MS-LCH); many patients with other forms of LCH, such as pulmonary (PLCH) do not necessarily need antineoplastic treatment.''
 +
=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.'''
 +
==[https://www.eurohistio.net/index_eng.html Euro-Histio-Net]==
 +
 +
*'''2013:''' Girschikofsky et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667012/ Management of adult patients with Langerhans cell histiocytosis: Recommendations from an expert panel on behalf of Euro-Histio-Net] [https://pubmed.ncbi.nlm.nih.gov/23672541/ PubMed]
 +
*'''2013:''' Haupt et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4557042/ Langerhans cell histiocytosis (LCH): Guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years] [https://www.ncbi.nlm.nih.gov/pubmed/23109216 PubMed]
 +
 +
==International Expert Consensus==
 +
*'''2022:''' Goyal et al. [https://doi.org/10.1182/blood.2021014343 International expert consensus recommendations for the diagnosis and treatment of Langerhans cell histiocytosis in adults] [https://www.ncbi.nlm.nih.gov/pubmed/35271698 PubMed]
  
−
=All lines of therapy=
+
==[https://www.nccn.org NCCN]==
 +
*''NCCN does not currently have guidelines at this granular level; please see [https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1502 NCCN Guidelines - Histiocytic Neoplasms].''
  
−
==Cladribine monotherapy {{#subobject:da32fb|Regimen=1}}==
+
=Untreated=
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
==Cytarabine & Methotrexate (CYM) {{#subobject:b24b28|Regimen=1}}==
 +
CYM: '''<u>CY</u>'''tarabine, '''<u>M</u>'''ethotrexate
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:d51545|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/10.1002/ajh.25864 Cao et al. 2020 (MAALCH)]
 +
|2014-2018
 +
|style="background-color:#91cf61"|Phase 2
 
|-
 
|-
−
|[[#top|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
===Regimen {{#subobject:1ef1c0|Variant=1}}===
+
====Chemotherapy====
−
{| border="1" style="text-align:center;" !align="left"  
+
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 500 mg/m<sup>2</sup>)
−
|'''Study'''
+
*[[Methotrexate (MTX)]] 1000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
'''35-day cycle for 6 cycles'''
 +
</div></div>
 +
===References===
 +
#'''MAALCH:''' Cao XX, Li J, Zhao AL, He TH, Gao XM, Cai HC, Zhang L, Zhang Y, Feng J, Zhu TN, Niu N, Sun J, Liang ZY, Duan MH, Zhou DB. Methotrexate and cytarabine for adult patients with newly diagnosed Langerhans cell histiocytosis: A single arm, single center, prospective phase 2 study. Am J Hematol. 2020 Sep;95(9):E235-E238. Epub 2020 Jun 20. [https://doi.org/10.1002/ajh.25864 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32395858/ PubMed] [https://clinicaltrials.gov/study/NCT02389400 NCT02389400]
 +
==Etoposide & Prednisone {{#subobject:566a87|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:#3c6b84|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://onlinelibrary.wiley.com/doi/10.1002/pbc.22229/abstract Weitzman et al. 2009 (LCH-S-98)]
+
|[https://doi.org/10.1067/mpd.2001.111331 Gadner et al. 2001 (LCH-I)]
−
|style="background-color:#EEEE00"|Phase II
+
|1991-1995
 +
|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
 +
|[[#Vinblastine_.26_Prednisone|Vinblastine & Prednisone]]
 +
|style="background-color:#ffffbf"|Did not meet efficacy endpoints
 
|-
 
|-
 
|}
 
|}
−
To be completed
+
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cladribine (Leustatin)]]
+
*[[Etoposide (Vepesid)]] 150 mg/mg<sup>2</sup> IV once per day on days 1 to 3
−
 
+
====Glucocorticoid therapy====
 +
*[[Prednisone (Sterapred)]] as follows:
 +
**Cycles 1: (dose/route not specified) once
 +
'''21-day cycle for 8 cycles'''
 +
</div></div>
 
===References===
 
===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]
+
# 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. [https://doi.org/10.1067/mpd.2001.111331 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/11343051/ PubMed]
  
−
==Cladribine & Cytarabine {{#subobject:4c5b41|Regimen=1}}==
+
==Etoposide, Vinblastine, Prednisone {{#subobject:5145a8|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:#7ace0e|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1182/blood-2007-08-106211 Gadner et al. 2007 (LCH-II)]
 +
|1996-2001
 +
|style="background-color:#1a9851"|Phase 3 (E-esc)
 +
|[[#Vinblastine_.26_Prednisone|Vinblastine & Prednisone]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of rapid response
 
|-
 
|-
−
|[[#top|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
===Regimen {{#subobject:7b85e8|Variant=1}}===
+
====Chemotherapy====
−
{| border="1" style="text-align:center;" !align="left"  
+
*[[Etoposide (Vepesid)]] as follows:
−
|'''Study'''
+
**Cycle 1: 150 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
**Cycles 2 to 7: 150 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
*[[Vinblastine (Velban)]] as follows:
 +
**Cycle 1: 6 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, 29, 36
 +
**Cycles 2 to 7: 6 mg/m<sup>2</sup> IV bolus once on day 1
 +
====Glucocorticoid therapy====
 +
*[[Prednisone (Sterapred)]] as follows:
 +
**Cycle 1: 40 mg/m<sup>2</sup>/day split three times per day for 4 weeks, then tapering off over 2 weeks
 +
**Cycles 2 to 7: 40 mg/m<sup>2</sup>/day split three times per day on days 1 to 5
 +
'''6-week course, then 21-day cycle for 6 cycles'''
 +
</div></div>
 +
===References===
 +
# '''LCH-II:''' 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. [https://doi.org/10.1182/blood-2007-08-106211 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18089850/ PubMed] ISRCTN57679341
 +
==Methotrexate, Vinblastine, Prednisone {{#subobject:2d772c|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:#f569ce|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624454/ Donadieu et al. 2015]
+
|[https://doi.org/10.1182/blood-2012-09-455774 Gadner et al. 2013 (LCH-III)]
−
|style="background-color:#EEEE00"|Phase II
+
|2001-2008
 +
|style="background-color:#1a9851"|Phase 3 (E-esc)
 +
|[[#Vinblastine_.26_Prednisone|Vinblastine & Prednisone]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of early progression at week 6 and response at week 12
 
|-
 
|-
 
|}
 
|}
−
====Chemotherapy, induction====
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[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'''
+
====Chemotherapy====
−
**Children weighing less than 10 kg received a dose of 0.3 mg/kg/day
+
*[[Methotrexate (MTX)]] 500 mg/m<sup>2</sup> IV once per day on days 1, 15, 29
−
*[[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'''
+
*[[Vinblastine (Velban)]] 6 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, 29, 36
−
 
+
====Glucocorticoid therapy====
−
'''35-day cycle for 2 or more cycles'''
+
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup>/day PO on days 1 to 28, then tapered off by day 42
−
 
+
'''6-week course'''
−
''Patients with a "good response" proceeded to consolidation therapy:''
+
</div>
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
====Chemotherapy, consolidation====
+
====Subsequent treatment====
−
*[[Cladribine (Leustatin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 3
+
*See paper for details of treatment beyond induction.
−
 
+
</div></div>
−
'''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===
 
===References===
−
<!-- Preliminary data from this study were presented orally at the 30th meeting of the Histiocyte Society, Washington, DC, 22 October 2013. -->
+
# '''LCH-III:''' 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. [https://doi.org/10.1182/blood-2012-09-455774 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23589673/ PubMed] [https://clinicaltrials.gov/study/NCT00276757 NCT00276757]
−
# 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}}==
+
==Vinblastine & Prednisone {{#subobject:378322|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:#bf6a74|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1067/mpd.2001.111331 Gadner et al. 2001 (LCH-I)]
 +
|1991-1995
 +
|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
 +
|[[#Etoposide_.26_Prednisone|Etoposide & Prednisone]]
 +
|style="background-color:#ffffbf"|Did not meet efficacy endpoints
 
|-
 
|-
−
|[[#top|back to top]]
+
|[https://doi.org/10.1182/blood-2007-08-106211 Gadner et al. 2007 (LCH-II)]
−
|}
+
|1996-2001
−
 
+
|style="background-color:#1a9851"|Phase 3 (C)
−
===Regimen {{#subobject:#3c6b84|Variant=1}}===
+
|[[#Etoposide.2C_Vinblastine.2C_Prednisone|Etoposide, Vinblastine, Prednisone]]
−
{| border="1" style="text-align:center;" !align="left"
+
|style="background-color:#ffffbf"|Did not meet primary endpoint of rapid response
−
|'''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)]
+
|[https://doi.org/10.1182/blood-2012-09-455774 Gadner et al. 2013 (LCH-III)]
−
|style="background-color:#00CD00"|Phase III
+
|2001-2008
−
|[[Histiocytoses#Vinblastine_.26_Prednisone|Vinblastine & Prednisone]]
+
|style="background-color:#1a9851"|Phase 3 (C)
−
|style="background-color:#ffffbf"|Seems not superior
+
|[[#Methotrexate.2C_Vinblastine.2C_Prednisone|Methotrexate, Vinblastine, Prednisone]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of early progression at week 6 and response at week 12
 
|-
 
|-
 
|}
 
|}
−
To be completed
+
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Etoposide (Vepesid)]]
+
*[[Vinblastine (Velban)]] as follows:
−
*[[Prednisone (Sterapred)]]
+
**Cycle 1: 6 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, 29, 36
−
 
+
**Cycles 2 to 7: 6 mg/m<sup>2</sup> IV bolus once on day 1
 +
====Glucocorticoid therapy====
 +
*[[Prednisone (Sterapred)]] as follows:
 +
**Cycle 1: 40 mg/m<sup>2</sup>/day split three times per day for 4 weeks, then tapering off over 2 weeks
 +
**Cycles 2 to 7: 40 mg/m<sup>2</sup>/day split three times per day on days 1 to 5
 +
'''6-week course, then 21-day cycle for 6 cycles'''
 +
</div></div>
 
===References===
 
===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]
+
# '''LCH-I:''' 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. [https://doi.org/10.1067/mpd.2001.111331 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11343051/ PubMed]
−
 
+
# '''LCH-II:''' 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. [https://doi.org/10.1182/blood-2007-08-106211 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18089850/ PubMed] ISRCTN57679341
−
==Etoposide, Vinblastine, Prednisone {{#subobject:5145a8|Regimen=1}}==
+
# '''LCH-III:''' 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. [https://doi.org/10.1182/blood-2012-09-455774 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23589673/ PubMed] [https://clinicaltrials.gov/study/NCT00276757 NCT00276757]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
=Relapsed or refractory=
 +
==Cladribine monotherapy {{#subobject:da32fb|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:1ef1c0|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/10.1002/pbc.22229 Weitzman et al. 2009 (LCH-S-98)]
 +
|1999-04 to NR
 +
|style="background-color:#91cf61"|Phase 2
 
|-
 
|-
−
|[[#top|back to top]]
 
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cladribine (Leustatin)]] 5 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5
 +
'''21-day cycle for up to 6 cycles'''
 +
</div></div>
 +
===References===
 +
# '''LCH-S-98:''' 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. [https://doi.org/10.1002/pbc.22229 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19731321/ PubMed]
  
−
===Regimen {{#subobject:#7ace0e|Variant=1}}===
+
==Cladribine & Cytarabine {{#subobject:4c5b41|Regimen=1}}==
−
{| border="1" style="text-align:center;" !align="left"  
+
<div class="toccolours" style="background-color:#eeeeee">
−
|'''Study'''
+
===Regimen {{#subobject:7b85e8|Variant=1}}===
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
|'''Comparator'''
+
!style="width: 33%"|Study
−
|[[Levels_of_Evidence#Efficacy|'''Efficacy''']]
+
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/111/5/2556.long Gadner et al. 2007 (LCH-II)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624454/ Donadieu et al. 2015 (LCH-S-2005)]
−
|style="background-color:#00CD00"|Phase III
+
|2005-04 to 2010-11
−
|[[Histiocytoses#Vinblastine_.26_Prednisone|Vinblastine & Prednisone]]
+
|style="background-color:#91cf61"|Phase 2
−
|style="background-color:#ffffbf"|Seems not superior
 
 
|-
 
|-
 
|}
 
|}
−
''Total duration of therapy is 24 weeks.''
+
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy, initial====
+
====Chemotherapy====
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV over 1 hour once per week
+
*[[Cladribine (Leustatin)]] by the following weight-based criteria:
−
*[[Vinblastine (Velban)]] 6 mg/m<sup>2</sup> IV bolus once per week
+
**10 kg or more: 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'''
−
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup>/day split TID for 4 weeks, then tapering off over 2 weeks
+
**Less than 10 kg: 0.3 mg/kg IV over 2 hours once per day on days 2 to 6, '''should not be administered simultaneously with cytarabine'''
−
 
+
*[[Cytarabine (Ara-C)]] 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'''
−
'''6-week course, followed by:'''
+
'''35-day cycle for 2 or more cycles'''
−
 
+
</div>
−
====Chemotherapy, continuation====
+
<div class="toccolours" style="background-color:#cbd5e7">
−
*[[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'''
 
  
 +
====Subsequent treatment====
 +
*LCH-S-2005, patients with a good response: [[#Cladribine_monotherapy_2|Cladribine]] consolidation
 +
</div></div>
 
===References===
 
===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]
+
<!-- Preliminary data from this study were presented orally at the 30th meeting of the Histiocyte Society, Washington, DC, 22 October 2013. -->
−
 
+
# '''LCH-S-2005:''' 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. [https://doi.org/10.1182/blood-2015-03-635151 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624454/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26194764/ PubMed]
−
==Methotrexate, Vinblastine, Prednisone {{#subobject:2d772c|Regimen=1}}==
+
==Cobimetinib monotherapy {{#subobject:a6f6dd|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:#fecb7f|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 
|-
 
|-
−
|[[#top|back to top]]
 
 
|}
 
|}
−
 
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
===Regimen {{#subobject:#f569ce|Variant=1}}===
+
!style="width: 33%"|Study
−
{| border="1" style="text-align:center;" !align="left"  
+
!style="width: 33%"|Dates of enrollment
−
|'''Study'''
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
|[[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)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438729/ Diamond et al. 2019 (MSK 15-216)]
−
|style="background-color:#00CD00"|Phase III
+
|2016-NR
−
|[[Histiocytoses#Vinblastine_.26_Prednisone|Vinblastine & Prednisone]]
+
|style="background-color:#ffffbe"|Phase 2, fewer than 20 pts in this arm (RT)
−
|style="background-color:#ffffbf"|Seems not superior
 
 
|-
 
|-
 
|}
 
|}
−
To be completed
+
''Note: there were N=2 patients with LCH; it was unclear if they were untreated or previously treated.''
−
====Chemotherapy====
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Methotrexate (MTX)]]
+
====Targeted therapy====
−
*[[Vinblastine (Velban)]]
+
*[[Cobimetinib (Cotellic)]] 60 mg PO once per day on days 1 to 21
−
*[[Prednisone (Sterapred)]]
+
'''28-day cycles'''
−
 
+
</div></div>
 
===References===
 
===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]
+
# '''MSK 15-216:''' Diamond EL, Durham BH, Ulaner GA, Drill E, Buthorn J, Ki M, Bitner L, Cho H, Young RJ, Francis JH, Rampal R, Lacouture M, Brody LA, Ozkaya N, Dogan A, Rosen N, Iasonos A, Abdel-Wahab O, Hyman DM. Efficacy of MEK inhibition in patients with histiocytic neoplasms. Nature. 2019 Mar;567(7749):521-524. Epub 2019 Mar 13. [https://doi.org/10.1038/s41586-019-1012-y link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438729/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30867592/ PubMed] [https://clinicaltrials.gov/study/NCT02649972 NCT02649972]
−
 
 
 
==Vemurafenib monotherapy {{#subobject:953978|Regimen=1}}==
 
==Vemurafenib monotherapy {{#subobject:953978|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
 
 
 
===Regimen {{#subobject:#73ec1b|Variant=1}}===
 
===Regimen {{#subobject:#73ec1b|Variant=1}}===
−
{| border="1" style="text-align:center;" !align="left"  
+
{| class="wikitable" style="width: 60%; text-align:center;"  
−
|'''Study'''
+
!style="width: 33%"|Study
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971773/ Hyman et al. 2015]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971773/ Hyman et al. 2015 (VE-BASKET)]
−
|style="background-color:#ff0000"|Phase II, <20 pts in this arm
+
|2012-2014
 +
|style="background-color:#ffffbe"|Phase 2, fewer than 20 pts in this arm
 
|-
 
|-
 
|}
 
|}
−
''This was part of a basket trial, all patients had BRAF V600E mutations.''
+
''Note: This was part of a basket trial, all patients had BRAF p.V600E mutations. A minority (7/18, 39%) of participants were untreated.''
−
====Chemotherapy====
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Vemurafenib (Zelboraf)]] 960 mg PO BID
+
====Targeted therapy====
−
 
+
*[[Vemurafenib (Zelboraf)]] 960 mg PO twice per day
 
'''Duration of treatment not specified'''
 
'''Duration of treatment not specified'''
−
 
+
</div></div>
 
===References===
 
===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]
+
# '''VE-BASKET:''' 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. [https://doi.org/10.1056/NEJMoa1502309 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971773/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26287849/ PubMed]
−
 
+
=Relapsed or refractory, consolidation=
−
==Vinblastine & Prednisone {{#subobject:378322|Regimen=1}}==
+
==Cladribine monotherapy {{#subobject:7db44f|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:77d734|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://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624454/ Donadieu et al. 2015 (LCH-S-2005)]
 +
|2005-04 to 2010-11
 +
|style="background-color:#91cf61"|Phase 2
 
|-
 
|-
−
|[[#top|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
===Regimen {{#subobject:#bf6a74|Variant=1}}===
+
====Preceding treatment====
−
{| border="1" style="text-align:center;" !align="left"
+
*Salvage [[#Cladribine_.26_Cytarabine|Cladribine & Cytarabine]]
−
|'''Study'''
+
</div>
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
<div class="toccolours" style="background-color:#b3e2cd">
−
|'''Comparator'''
+
====Chemotherapy====
−
|[[Levels_of_Evidence#Efficacy|'''Efficacy''']]
+
*[[Cladribine (Leustatin)]] 5 mg/m<sup>2</sup> IV once per day on days 1 to 3
−
|-
+
'''21-day cycle for 2 cycles'''
−
|[http://www.jpeds.com/article/S0022-3476(01)07325-5/abstract Gadner et al. 2001 (LCH-I)]
+
</div>
−
|style="background-color:#00CD00"|Phase III
+
<div class="toccolours" style="background-color:#cbd5e7">
−
|[[Histiocytoses#Etoposide_.26_Prednisone|Etoposide & Prednisone]]
+
====Subsequent treatment====
−
|style="background-color:#ffffbf"|Seems not superior
+
*[[#Mercaptopurine.2C_Methotrexate.2C_Vinblastine.2C_Prednisolone|4-drug]] maintenance
−
|-
+
</div></div>
−
|[http://www.bloodjournal.org/content/111/5/2556.long Gadner et al. 2007 (LCH-II)]
+
===References===
−
|style="background-color:#00CD00"|Phase III
+
<!-- Preliminary data from this study were presented orally at the 30th meeting of the Histiocyte Society, Washington, DC, 22 October 2013. -->
−
|[[Histiocytoses#Etoposide.2C_Vinblastine.2C_Prednisone|Etoposide, Vinblastine, Prednisone]]
+
# '''LCH-S-2005:''' 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. [https://doi.org/10.1182/blood-2015-03-635151 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624454/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26194764/ PubMed]
−
|style="background-color:#ffffbf"|Seems not superior
+
=Relapsed or refractory, maintenance=
 +
==Mercaptopurine, Methotrexate, Vinblastine, Prednisolone {{#subobject:b3e901|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:231bee|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]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/121/25/5006.long Gadner et al. 2013 (LCH-III)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624454/ Donadieu et al. 2015 (LCH-S-2005)]
−
|style="background-color:#00CD00"|Phase III
+
|2005-04 to 2010-11
−
|[[Histiocytoses#Methotrexate.2C_Vinblastine.2C_Prednisone|Methotrexate, Vinblastine, Prednisone]]
+
|style="background-color:#91cf61"|Phase 2
−
|style="background-color:#ffffbf"|Seems not superior
 
 
|-
 
|-
 
|}
 
|}
−
''Total duration of therapy is 24 weeks, in LCH-II.''
+
<div class="toccolours" style="background-color:#cbd5e8">
−
====Chemotherapy, initial====
+
====Preceding treatment====
−
*[[Vinblastine (Velban)]] 6 mg/m<sup>2</sup> IV bolus once per week
+
*Salvage [[#Cladribine_monotherapy_2|Cladribine]] x 2
−
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup>/day split TID for 4 weeks, then tapering off over 2 weeks
+
</div>
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
'''6-week course, followed by:'''
+
====Chemotherapy====
−
 
+
*[[Mercaptopurine (6-MP)]] 50 mg/m<sup>2</sup> PO once per day on days 1 to 14
−
====Chemotherapy, continuation====
+
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once per day on days 1 & 8
−
*[[Vinblastine (Velban)]] 6 mg/m<sup>2</sup> IV bolus once on day 1
+
*[[Vinblastine (Velban)]] as follows:
−
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup>/day split TID on days 1 to 5
+
**Cycles 1 to 13: 6 mg/m<sup>2</sup> IV once on day 1
−
 
+
====Glucocorticoid therapy====
−
'''21-day cycle for 6 cycles'''
+
*[[Prednisolone (Millipred)]] as follows:
−
 
+
**Cycles 1 to 13: 40 mg/m<sup>2</sup> PO once per day on days 1 to 5
 +
'''14-day cycle for 39 cycles (18 months)'''
 +
</div></div>
 
===References===
 
===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]
+
<!-- Preliminary data from this study were presented orally at the 30th meeting of the Histiocyte Society, Washington, DC, 22 October 2013. -->
−
# 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]
+
# '''LCH-S-2005:''' 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. [https://doi.org/10.1182/blood-2015-03-635151 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624454/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26194764/ 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:Langerhans cell histiocytosis regimens]]
 
[[Category:Langerhans cell histiocytosis regimens]]
 
[[Category:Disease-specific pages]]
 
[[Category:Disease-specific pages]]
 
[[Category:Histiocytoses]]
 
[[Category:Histiocytoses]]

Latest revision as of 23:36, 24 June 2024

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Section editor
GauravGoyal.jpg
 Gaurav Goyal, MD
UAB
Birmingham, AL, USA
LinkedIn
11 regimens on this page
11 variants on this page


Note: the majority of the regimens on this page are intended for multi-system Langerhans cell histiocytosis (MS-LCH); many patients with other forms of LCH, such as pulmonary (PLCH) do not necessarily need antineoplastic treatment.

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.

Euro-Histio-Net

International Expert Consensus

NCCN

Untreated

Cytarabine & Methotrexate (CYM)

CYM: CYtarabine, Methotrexate

Regimen

Study Dates of enrollment Evidence
Cao et al. 2020 (MAALCH) 2014-2018 Phase 2

Chemotherapy

  • Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 500 mg/m2)
  • Methotrexate (MTX) 1000 mg/m2 IV continuous infusion over 24 hours, started on day 1

35-day cycle for 6 cycles

References

  1. MAALCH: Cao XX, Li J, Zhao AL, He TH, Gao XM, Cai HC, Zhang L, Zhang Y, Feng J, Zhu TN, Niu N, Sun J, Liang ZY, Duan MH, Zhou DB. Methotrexate and cytarabine for adult patients with newly diagnosed Langerhans cell histiocytosis: A single arm, single center, prospective phase 2 study. Am J Hematol. 2020 Sep;95(9):E235-E238. Epub 2020 Jun 20. link to original article contains dosing details in manuscript PubMed NCT02389400

Etoposide & Prednisone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gadner et al. 2001 (LCH-I) 1991-1995 Phase 3 (E-switch-ic) Vinblastine & Prednisone Did not meet efficacy endpoints

Chemotherapy

Glucocorticoid therapy

21-day cycle for 8 cycles

References

  1. 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. link to original article contains dosing details in abstract PubMed

Etoposide, Vinblastine, Prednisone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gadner et al. 2007 (LCH-II) 1996-2001 Phase 3 (E-esc) Vinblastine & Prednisone Did not meet primary endpoint of rapid response

Chemotherapy

  • Etoposide (Vepesid) as follows:
    • Cycle 1: 150 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36
    • Cycles 2 to 7: 150 mg/m2 IV over 60 minutes once on day 1
  • Vinblastine (Velban) as follows:
    • Cycle 1: 6 mg/m2 IV bolus once per day on days 1, 8, 15, 22, 29, 36
    • Cycles 2 to 7: 6 mg/m2 IV bolus once on day 1

Glucocorticoid therapy

  • Prednisone (Sterapred) as follows:
    • Cycle 1: 40 mg/m2/day split three times per day for 4 weeks, then tapering off over 2 weeks
    • Cycles 2 to 7: 40 mg/m2/day split three times per day on days 1 to 5

6-week course, then 21-day cycle for 6 cycles

References

  1. LCH-II: 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. link to original article contains dosing details in manuscript PubMed ISRCTN57679341

Methotrexate, Vinblastine, Prednisone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gadner et al. 2013 (LCH-III) 2001-2008 Phase 3 (E-esc) Vinblastine & Prednisone Did not meet primary endpoint of early progression at week 6 and response at week 12

Chemotherapy

Glucocorticoid therapy

6-week course

Subsequent treatment

  • See paper for details of treatment beyond induction.

References

  1. LCH-III: 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. link to original article contains dosing details in manuscript PubMed NCT00276757

Vinblastine & Prednisone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gadner et al. 2001 (LCH-I) 1991-1995 Phase 3 (E-switch-ic) Etoposide & Prednisone Did not meet efficacy endpoints
Gadner et al. 2007 (LCH-II) 1996-2001 Phase 3 (C) Etoposide, Vinblastine, Prednisone Did not meet primary endpoint of rapid response
Gadner et al. 2013 (LCH-III) 2001-2008 Phase 3 (C) Methotrexate, Vinblastine, Prednisone Did not meet primary endpoint of early progression at week 6 and response at week 12

Chemotherapy

  • Vinblastine (Velban) as follows:
    • Cycle 1: 6 mg/m2 IV bolus once per day on days 1, 8, 15, 22, 29, 36
    • Cycles 2 to 7: 6 mg/m2 IV bolus once on day 1

Glucocorticoid therapy

  • Prednisone (Sterapred) as follows:
    • Cycle 1: 40 mg/m2/day split three times per day for 4 weeks, then tapering off over 2 weeks
    • Cycles 2 to 7: 40 mg/m2/day split three times per day on days 1 to 5

6-week course, then 21-day cycle for 6 cycles

References

  1. LCH-I: 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. link to original article PubMed
  2. LCH-II: 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. link to original article contains dosing details in manuscript PubMed ISRCTN57679341
  3. LCH-III: 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. link to original article PubMed NCT00276757

Relapsed or refractory

Cladribine monotherapy

Regimen

Study Dates of enrollment Evidence
Weitzman et al. 2009 (LCH-S-98) 1999-04 to NR Phase 2

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. LCH-S-98: 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. link to original article contains dosing details in manuscript PubMed

Cladribine & Cytarabine

Regimen

Study Dates of enrollment Evidence
Donadieu et al. 2015 (LCH-S-2005) 2005-04 to 2010-11 Phase 2

Chemotherapy

  • Cladribine (Leustatin) by the following weight-based criteria:
    • 10 kg or more: 9 mg/m2 IV over 2 hours once per day on days 2 to 6, should not be administered simultaneously with cytarabine
    • Less than 10 kg: 0.3 mg/kg IV over 2 hours once per day on days 2 to 6, should not be administered simultaneously with cytarabine
  • Cytarabine (Ara-C) 500 mg/m2 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

Subsequent treatment

  • LCH-S-2005, patients with a good response: Cladribine consolidation

References

  1. LCH-S-2005: 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. link to original article contains dosing details in manuscript link to PMC article PubMed

Cobimetinib monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence
Diamond et al. 2019 (MSK 15-216) 2016-NR Phase 2, fewer than 20 pts in this arm (RT)

Note: there were N=2 patients with LCH; it was unclear if they were untreated or previously treated.

Targeted therapy

28-day cycles

References

  1. MSK 15-216: Diamond EL, Durham BH, Ulaner GA, Drill E, Buthorn J, Ki M, Bitner L, Cho H, Young RJ, Francis JH, Rampal R, Lacouture M, Brody LA, Ozkaya N, Dogan A, Rosen N, Iasonos A, Abdel-Wahab O, Hyman DM. Efficacy of MEK inhibition in patients with histiocytic neoplasms. Nature. 2019 Mar;567(7749):521-524. Epub 2019 Mar 13. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02649972

Vemurafenib monotherapy

Regimen

Study Dates of enrollment Evidence
Hyman et al. 2015 (VE-BASKET) 2012-2014 Phase 2, fewer than 20 pts in this arm

Note: This was part of a basket trial, all patients had BRAF p.V600E mutations. A minority (7/18, 39%) of participants were untreated.

Targeted therapy

Duration of treatment not specified

References

  1. VE-BASKET: 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 dosing details in manuscript link to PMC article PubMed

Relapsed or refractory, consolidation

Cladribine monotherapy

Regimen

Study Dates of enrollment Evidence
Donadieu et al. 2015 (LCH-S-2005) 2005-04 to 2010-11 Phase 2

Preceding treatment

Chemotherapy

21-day cycle for 2 cycles

Subsequent treatment

References

  1. LCH-S-2005: 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. link to original article contains dosing details in manuscript link to PMC article PubMed

Relapsed or refractory, maintenance

Mercaptopurine, Methotrexate, Vinblastine, Prednisolone

Regimen

Study Dates of enrollment Evidence
Donadieu et al. 2015 (LCH-S-2005) 2005-04 to 2010-11 Phase 2

Preceding treatment

Chemotherapy

Glucocorticoid therapy

14-day cycle for 39 cycles (18 months)

References

  1. LCH-S-2005: 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. link to original article contains dosing details in manuscript link to PMC article PubMed
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