Clinical trial NCT04773366: A Prospective Study for the Treatment of Children With Newly Diagnosed LCH Using a Cytarabine Contained Protocol
Official title: A Prospective Institutional Study for the Treatment of Children With Newly Diagnosed Langerhans Cell Histiocytosis Using a Cytarabine Contained Protocol
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Langerhans Cell Histiocytosis
Keywords: Langerhans cell histiocytosis
pediatric patients
cytarabine
treatment outcome
Lead sponsor: Shanghai Children's Medical Center
Sponsor class: OTHER
First posted: 2021-02-26
Enrollment: 200
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: All enrolled patients are stratified into 4 risk groups. Patients in each risk group are assigned to one treatment regimen.
Primary purpose: TREATMENT

Brief summary: From January 2010 to December 2014, 150 children with MS-LCH were treated in our hospital following a LCH II (Arm B) based protocol. Treatment was based on a modification of the LCH-II (Arm B) based protocol. However, the continuation treatment was extended to 56 weeks and etoposide was omitted from the continuation treatment.

For the 59 patients with RO involvement (RO+) (the lungs are not considered a RO in the current study), the rapid response rate (week 6) was 61.0% and the 3-year overall survival (OS) 73.4±5.9%. Rapid responders had a better 3-year survival rate than poor responders (90.9±5.0% vs. 45.7±11.0%, P\<0.001). The 3-year OS in the current study is 10\~20% lower than the rates reported by Gadner et al. and Morimoto et al.. We have not yet adopted effective salvage therapies for RO+ patients with recurrent disease. During the time of this study, cladribine was unavailable. Second-line therapy for non-responders or patients with disease reactivation was individualized treatment based on the physician's experience. An effective salvage therapy is essential for this high-risk group.

For 91without RO involvement (RO-), 78 patients (85.7%) were rapid responders at week 6. The 3-year cumulative reactivation rate was 10.7% for RO- patients. No death occurred in this subgroup, with a 3-year OS of 100% in RO- patients. Compared to the LCH II and LCH III trials, the current study had a more intensive initial treatment regimen for RO- patients. However, the addition of etoposide to prednisone and vincristine in the initial therapy did not increase the 6-week response rate for RO- patients (85.7% in this study compared to 83% in the LCH II study and 86% in the LCH III study). Surprisingly, with a relatively intense initial treatment, a relatively low 3-year cumulative reactivation rate was observed in RO- patients in the current study. This result suggests that the initial treatment intensity and duration of continuation therapy both impact disease reactivation. The intensity of induction can affect the degree of disease resolution. Insufficient treatment intensity might lead to late relapse. Similarity to that observed has been in other childhood hematological malignancies. This finding deserves to be tested in prospective clinical trials with long-term follow-up. Cytarabine has been applied for patients with LCH but has never been evaluated in our hospital prospectively. In this study, we administer a cytarabine contained protocol to patients with multisystem involvement with or without risk organs involvement. The treatment results will be compared with our historical studies.

Detailed description: All patients with de novo pathological confirmed LCH enrolled in this study will be classified into 4 groups. Group 1: Multisystem patients (≥2 organs/systems) with involvement of one or more "Risk" organs" (hematopoietic system, liver or spleen);Group 2:Multisystem patients, but without involvement of "Risk" organs; Group 3: Single system, Multifocal+ Single system, unifocal and special site@ (Isolated lesion of special site)+ Single system, unifocal and CNS risk+Single system, unifocal i.e. thyroid, lung, thymus, hypothalamic-pituitary+Single system, unifocal and other functionally critical anatomical sites; Group 4: Single system, unifocal i.e. bone, skin or lymph node (not the draining lymph node of another LCH lesion). For patients in Group 1, a 6-week initial treatment, a 16-week consolidation continuation treatment and a 26-week maintenance continuation treatment containing cytarabine is applied. For patients in Group 2, a 6-week initial treatment containing cytarabine and a 46-week continuation treatment (without cytarabine) is applied. For patients in Group 3,a 6-week initial treatment and a 46-week continuation treatment (without cytarabine) is applied. For patients in Group 4, only local therapy followed by wait-and-see strategy is applied.

Eligibility criteria: Inclusion Criteria:

1. Age under 18 years
2. Newly diagnosed LCH：Morphologic identification of the characteristic LCH cells, positive staining of the lesional cells with CD1α and/or Langerin
3. No congenital immunodeficiency, HIV infection, or prior organ transplant
4. No previous chemotherapy/target therapy/radiation, if any steroid applied, total prior steroids dosage \< prednisone 280 mg/m2

Exclusion Criteria:

* Patients have overwhelming infection, and a life expectancy of \< 2 weeks

Primary outcomes:
measure: Rate of responders after initial treatment for patients with risk organ involvement
timeFrame: Evaluation at week 6 or 12
measure: Reactivation rate for all patients
timeFrame: Up to 5 years
Secondary outcomes:
measure: Overall survival for patients with risk organ involvement
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Shanghai Children's Medical Center
Study officials:
affiliation: Shanghai Children's Medical Center
name: Yi-Jin Gao, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Simko SJ, McClain KL, Allen CE. Up-front therapy for LCH: is it time to test an alternative to vinblastine/prednisone? Br J Haematol. 2015 Apr;169(2):299-301. doi: 10.1111/bjh.13208. Epub 2014 Nov 16. No abstract available.
citation: Gadner H, Grois N, Potschger U, Minkov M, Arico 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. doi: 10.1182/blood-2007-08-106211. Epub 2007 Dec 18.
citation: Gadner H, Grois N, Arico M, Broadbent V, Ceci A, Jakobson A, Komp D, Michaelis J, Nicholson S, Potschger 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. doi: 10.1067/mpd.2001.111331.
citation: Egeler RM, de Kraker J, Voute PA. Cytosine-arabinoside, vincristine, and prednisolone in the treatment of children with disseminated Langerhans cell histiocytosis with organ dysfunction: experience at a single institution. Med Pediatr Oncol. 1993;21(4):265-70. doi: 10.1002/mpo.2950210406.
citation: Weitzman S, Braier J, Donadieu J, Egeler RM, Grois N, Ladisch S, Potschger 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. doi: 10.1002/pbc.22229.
citation: 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. doi: 10.1182/blood-2015-03-635151. Epub 2015 Jul 20.
citation: Braier J, Rosso D, Pollono D, Rey G, Lagomarsino E, Latella A, Zubizarreta P. Symptomatic bone langerhans cell histiocytosis treated at diagnosis or after reactivation with indomethacin alone. J Pediatr Hematol Oncol. 2014 Jul;36(5):e280-4. doi: 10.1097/MPH.0000000000000165001.
citation: Heritier S, Jehanne M, Leverger G, Emile JF, Alvarez JC, Haroche J, Donadieu J. Vemurafenib Use in an Infant for High-Risk Langerhans Cell Histiocytosis. JAMA Oncol. 2015 Sep;1(6):836-8. doi: 10.1001/jamaoncol.2015.0736. No abstract available.
citation: Gao YJ, Su M, Tang JY, Pan C, Chen J. Treatment Outcome of Children With Multisystem Langerhans Cell Histiocytosis: The Experience of a Single Children's Hospital in Shanghai, China. J Pediatr Hematol Oncol. 2018 Jan;40(1):e9-e12. doi: 10.1097/MPH.0000000000001016.
citation: Su M, Gao YJ, Pan C, Chen J, Tang JY. Outcome of children with Langerhans cell histiocytosis and single-system involvement: A retrospective study at a single center in Shanghai, China. Pediatr Hematol Oncol. 2018 Oct-Nov;35(7-8):385-392. doi: 10.1080/08880018.2018.1545814. Epub 2019 Jan 29.
citation: Gadner H, Minkov M, Grois N, Potschger U, Thiem E, Arico 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. doi: 10.1182/blood-2012-09-455774. Epub 2013 Apr 15.