A Prospective Study for the Treatment of Children With Newly Diagnosed LCH Using a Cytarabine Contained Protocol

Sponsor

Shanghai Children's Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT04773366

Collaborator

(none)

200

Enrollment

Location

Arms

Anticipated Duration (Months)

2.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Langerhans Cell Histiocytosis	Drug: Prednisone+Cytarabine+vincristine Drug: Prednisone+Cytarabine+vincristine+Mercaptopurine Drug: Prednisone+Cytarabine+vincristine+Mercaptopurine Drug: Prednisone+Cytarabine+vincristine Drug: Prednisone+vincristine+Mercaptopurine Drug: Prednisone+vincristine Drug: Prednisone+vincristine Other: Local therapy	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

200 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

All enrolled patients are stratified into 4 risk groups. Patients in each risk group are assigned to one treatment regimen.All enrolled patients are stratified into 4 risk groups. Patients in each risk group are assigned to one treatment regimen.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Prospective Institutional Study for the Treatment of Children With Newly Diagnosed Langerhans Cell Histiocytosis Using a Cytarabine Contained Protocol

Actual Study Start Date :

Jul 1, 2018

Anticipated Primary Completion Date :

Jun 30, 2023

Anticipated Study Completion Date :

Jun 30, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1 Multisystem patients (≥2 organs/systems) with involvement of one or more "Risk" organs, i.e. hematopoietic system, liver or spleen. All patients in this group receive an initial therapy (Week 1~6) followed by a consolidation continuation therapy (Week 7~22) and maintenance continuation therapy (Week 25~52).	Drug: Prednisone+Cytarabine+vincristine Group 1 initial treatment (W1~W6). Prednisone 40mg/m2×4w, taper 2w; Vincristine 1.5mg/m2 iv d1 of w1,2,3,4,5,6; Cytarabine 100mg/m2 iv/IH d1-4 q2w (w1,3,5) Drug: Prednisone+Cytarabine+vincristine+Mercaptopurine Group 1 Consolidation continuation treatment (W7~W22) . Prednisone 40mg/m2 d1-5 q3w (w7,10,13,16,19,22); VCR 1.5/m2 iv d1 q3w (w7,10,13,16,19,22); Cytarabine 100mg/m2 iv/IH d1-4 q3w (w7,10,13,16,19,22); 6-MP 50mg/m2/d,po,qn Drug: Prednisone+Cytarabine+vincristine+Mercaptopurine Group 1 Maintenance continuation treatment (W25~52) . Prednisone 40mg/m2 d1-5 q3w; Vincristine 1.5/m2 iv d1 q3w; Cytarabine 100mg/m2 iv/IH d1-4 q6w ×3 times (w25,31,37); 6-MP 50mg/m2/d,po,qn
Experimental: Group 2 Multisystem patients, but without involvement of "Risk" organs. All patients in this group receive an initial therapy (Week 1~6) followed by continuation therapy (Week 7~52).	Drug: Prednisone+Cytarabine+vincristine Group 2 Initial treatment (W1~W6) . Prednisone 40mg/m2×4w, taper 2w; Vincristine 1.5mg/m2 iv d1 of w1,2,3,4,5,6; Cytarabine 100mg/m2 iv/IH d1-4 q2w (w1,3,5) Drug: Prednisone+vincristine+Mercaptopurine Group 2 continuation treatment (W7~W52) . Prednisone 40mg/m2 d1-5 q3w; VCR 1.5/m2 iv d1 q3w; 6-MP 50mg/m2/d,po,qn
Experimental: Group 3 Includes patients with single system, multifocal or with single system, unifocal and special site (Isolated lesion of special site) or with single system, unifocal and CNS risk or with single system, unifocal i.e. thyroid, lung, thymus, hypothalamic-pituitary or with single system, unifocal and other functionally critical anatomical sites. All patients in this group receive an initial therapy (Week 1~6) followed by continuation therapy (Week 7~52).	Drug: Prednisone+vincristine Group 3 Initial treatment (W1~W6) . Prednisone 40mg/m2×4w, taper 2w; Vincristine 1.5mg/m2 iv d1 of w1,2,3,4,5,6 Drug: Prednisone+vincristine . Group 3 Continuation treatment (W7~W52)Prednisone 40mg/m2 d1-5 q3w; Vincristine 1.5/m2 iv d1 q3w
Experimental: Group 4 Patients with single system, unifocal i.e. bone, skin or lymph node (not the draining lymph node of another LCH lesion). All patients in this group enter into observation after local therapy. Chemotherapy only apply to patients with disease reactivation during observation.	Other: Local therapy Local therapy/wait and see. Group 4

Outcome Measures

Primary Outcome Measures

Rate of responders after initial treatment for patients with risk organ involvement [Evaluation at week 6 or 12]
Rate of responders after initial treatment and consolidation continuation treatment. A good response is defined as complete resolution (no evidence of active disease) in risk organs.
Reactivation rate for all patients [Up to 5 years]
Reactivation is defined as progression or relapse in any organ or system after disease complete resolution (no evidence of active disease).

Secondary Outcome Measures

Overall survival for patients with risk organ involvement [Up to 5 years]
Overall survival is measured using the Kaplan-Meier method. From the day of diagnosis to death for any reason or to the date of the last follow-up contact.

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Day to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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