Langerhans cell histiocytosis

Section editor
	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

• 2013: Girschikofsky et al. Management of adult patients with Langerhans cell histiocytosis: Recommendations from an expert panel on behalf of Euro-Histio-Net PubMed
• 2013: Haupt et al. Langerhans cell histiocytosis (LCH): Guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years PubMed

International Expert Consensus

• 2022: Goyal et al. International expert consensus recommendations for the diagnosis and treatment of Langerhans cell histiocytosis in adults PubMed

NCCN

• NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Histiocytic Neoplasms.

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

• Etoposide (Vepesid) 150 mg/mg² 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

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

• Methotrexate (MTX) 500 mg/m² IV once per day on days 1, 15, 29
• Vinblastine (Velban) 6 mg/m² IV bolus once per day on days 1, 8, 15, 22, 29, 36

Glucocorticoid therapy

• Prednisone (Sterapred) 40 mg/m²/day PO on days 1 to 28, then tapered off by day 42

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

• Cladribine (Leustatin) 5 mg/m² IV over 2 hours once per day on days 1 to 5

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

• Cobimetinib (Cotellic) 60 mg PO once per day on days 1 to 21

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

• Vemurafenib (Zelboraf) 960 mg PO twice per day

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

• Salvage Cladribine & Cytarabine

Chemotherapy

• Cladribine (Leustatin) 5 mg/m² IV once per day on days 1 to 3

21-day cycle for 2 cycles

Subsequent treatment

• 4-drug maintenance

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

• Salvage Cladribine x 2

Chemotherapy

• Mercaptopurine (6-MP) 50 mg/m² PO once per day on days 1 to 14
• Methotrexate (MTX) 20 mg/m² PO once per day on days 1 & 8
• Vinblastine (Velban) as follows:
  • Cycles 1 to 13: 6 mg/m² IV once on day 1

Glucocorticoid therapy

• Prednisolone (Millipred) as follows:
  • Cycles 1 to 13: 40 mg/m² PO once per day on days 1 to 5

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