Combination Therapy for Langerhans Cell Histiocytosis

Recruiting at 40 trial locations

Overseen By Adrienne English, BSN, RN

Age: < 65

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: North American Consortium for Histiocytosis

Disqualifiers: Pregnancy, Prior systemic therapy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

1400 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial uses a combination of two drugs, vinblastine and prednisone, to treat children with Langerhans Cell Histiocytosis. The treatment works by stopping abnormal cell growth and reducing inflammation. Vinblastine and prednisone have been used in various combinations to treat Langerhans Cell Histiocytosis (LCH) with some success in managing symptoms and achieving remission.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is the combination therapy of cladribine and cytarabine safe for treating Langerhans cell histiocytosis?

The combination of cladribine and cytarabine has shown significant activity in treating refractory Langerhans cell histiocytosis, but it can cause severe side effects, including grade 4 hematological toxicity (serious blood-related side effects) and has been associated with septic deaths in some cases. However, in another study, intermediate-dose cytarabine with or without cladribine was found to be effective and safe, with a good long-term prognosis, although some patients experienced grade 3 or 4 myelosuppression (a decrease in bone marrow activity leading to fewer blood cells). ^{1 2 3 4 5}

What makes the combination drug therapy for Langerhans Cell Histiocytosis unique?

This combination drug therapy is unique because it includes a mix of drugs like cytosine arabinoside, which is effective for patients unresponsive to standard treatments, and combines it with other drugs like vinblastine and prednisone that are commonly used. This approach aims to intensify treatment, potentially improving outcomes for patients with more severe forms of the disease. ^{2 5 6 7 8}

What evidence supports the effectiveness of the drugs used in the combination therapy for Langerhans Cell Histiocytosis?

Research shows that cladribine (2-chlorodeoxyadenosine) is effective in treating relapsed forms of Langerhans Cell Histiocytosis, and standard therapies like vinblastine and prednisone have been used successfully, especially when combined with other drugs like methotrexate and mercaptopurine. Intensified treatment regimens have also been shown to improve outcomes in patients with multisystem Langerhans Cell Histiocytosis. ^{2 5 6 7 9}

Research Team

Milen Minkov, MD, Ph.D

Principal Investigator

Children's Cancer Research Institute / St. Anna Children's Hospital

Carlos Rodriguez-Galindo, MD

Principal Investigator

North American Consortium for Histiocytosis

Eligibility Criteria

This trial is for children and adolescents under 18 with Langerhans Cell Histiocytosis (LCH). They must have a confirmed diagnosis, not be pregnant or breastfeeding, and have no prior systemic therapy. Participants need consent from parents/guardians if underage. Certain severe organ dysfunctions or infections may disqualify them.

Inclusion Criteria

My diagnosis of Langerhans cell histiocytosis is confirmed by tissue examination.

My diagnosis of Langerhans cell histiocytosis is confirmed by tissue analysis.

My non-risk organs are at least intermediate AD or my risk organs are better AD after 12 weeks.

Exclusion Criteria

I do not have lung failure, liver issues, or lung fibrosis due to LCH. I am not pregnant, breastfeeding, and I can sign consent.

I have Langerhans Cell Histiocytosis with specific brain or bone involvement.

My LCH is worsening in critical organs but shows no active signs, and I or my guardian haven't consented in writing.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

First-line Treatment

Combination therapy with vinblastine and prednisone for MS-LCH patients and SS-LCH with multifocal bone or CNS-risk lesions

6-12 weeks

Second-line Treatment

Intensive 24-week course with prednisolone, vincristine, and cytosine-arabinoside, followed by continuation therapy up to 24 months

24 months

Salvage Treatment

Salvage treatment for risk LCH with 2-CdA/Ara-C for patients failing first-line therapy

9 weeks

Stem Cell Transplantation

Reduced intensity conditioning hematopoietic stem cell transplantation for risk LCH patients failing previous therapies

3 years

Follow-up

Long-term follow-up for reactivation or permanent consequences after complete disease resolution

2 years

Treatment Details

Interventions

• 2-chlorodeoxyadenosine
• Cytosine Arabinoside
• hematopoietic stem cell transplantation (RIC-HSCT)
• INDOMETHACIN
• Intravenous immunoglobulin
• Mercaptopurine
• Methotrexate
• Prednisone
• Vinblastine

Trial Overview The study tests various treatments including Prednisone, stem cell transplantation, immunoglobulin, INDOMETHACIN, mercaptopurine, Cytosine Arabinoside, Vinblastine, Methotrexate and 2-chlorodeoxyadenosine in young patients with LCH to find the most effective approach.

Participant Groups

Group I: Stratum VI Experimental Treatment 6 Interventions

Natural history and management of "other" SS-LCH not eligible for stratum I group 2. * Treatment Options- Management (mostly "wait \& see" and topical treatment) is left to the discretion of the treating physician. All treatments and disease responses must be reported in the database. In the case of uncertainties please contact your National Coordinator. * Patients being followed on Stratum VI who have progression of disease to MSLCH, multifocal bone disease or CNS-risk bone lesions should be enrolled on Stratum I therapy. * Patients being followed on Stratum VI who develop isolated tumorous or neurodegenerative CNS-LCH should be enrolled on Stratum V.

Group II: Stratum V Experimental Treatment 3 Interventions

Stratum V Monitoring and Treatment of isolated tumorous and neurodegenerative CNS-LCH - Special regimens will be offered to patients with isolated tumorous CNS-LCH (repeated 2-CdA courses) and to patients with clinically manifested ND-CNS-LCH (+/- extracranial LCH manifestations). For the last group monotherapy with Ara-C courses or (Intravenous immunoglobulin)IVIG will be offered depending on physician's choice.

Group III: Stratum IV Experimental Treatment 1 Intervention

To determine the overall and disease free survival at 1 and 3 years after reduced intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT). Salvage treatment option for MS-LCH patients with risk organ involvement, who fail to respond to front-line therapy (Stratum I) OR to the salvage 2- CdA/Ara-C regimen (Stratum III).

Group IV: Stratum III Experimental Treatment 1 Intervention

Salvage treatment for risk LCH To assess the efficacy of the combination 2-CdA/Ara-C (Cytosine Arabinoside and 2-chlorodeoxyadenosine) in MS-LCH (patients with risk organ involvement, who fail to respond to front-line (Stratum I) therapy. The initial therapy consists of 2 courses of 2-CdA/Ara-C. Continuation of outlined treatment to be assessed at assigned intervals in each stratum.

Group V: Stratum II Experimental Treatment 6 Interventions

A uniform "intensive" 24-week course consisting of prednisolone, vincristine and cytosine-arabinoside will be introduced in Stratum II for eligible patients. It will be followed by a continuation therapy to total treatment duration of 24 months. Participants who after SL-IT (week 24) have a response (NAD or AD better) are eligible for randomization between the continuation arms "INDOMETHACIN" and "6-MP/MTX" (mercaptopurine and Methotrexate).

Group VI: Stratum I Experimental Treatment 3 Interventions

Stratum I The combination of Prednisone and vinblastine is the standard first-line combination for patients needing systemic therapy (Stratum I). Patients with MS-LCH and involvement of risk organs, who do not respond to 6-12 weeks of standard therapy, will be immediately switched to alternative treatment approaches (Stratum III or Stratum IV). Further therapy prolongation (12 vs. 24 months) and intensification (± mercaptopurine) will further reduce the reactivation rate and the permanent consequences.

Cytosine Arabinoside is already approved in United States, European Union, Japan for the following indications:

Approved in United States as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myelogenous leukemia
• Non-Hodgkin's lymphoma

Approved in European Union as Cytarabine for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myelogenous leukemia
• Non-Hodgkin's lymphoma

Approved in Japan as Cytarabine for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myelogenous leukemia
• Non-Hodgkin's lymphoma

Who Is Running the Clinical Trial?

North American Consortium for Histiocytosis

Lead Sponsor

Trials

5

Recruited

1,700+

Histiocyte Society

Collaborator

Trials

2

Recruited

1,800+

Findings from Research

Standard treatment for Langerhans cell histiocytosis typically involves vinblastine and prednisone, with additional medications like methotrexate or mercaptopurine based on disease severity.

For patients who do not respond to standard therapies, options like cytosine arabinoside and cladribine are effective, and emerging treatments include monoclonal antibodies targeting specific markers on Langerhans cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug therapy for the treatment of Langerhans cell histiocytosis. McClain, KL.[2022]

Both the vindesine and prednisone (VP) regimen and the cyclophosphamide, etoposide, vindesine, and prednisone (CEVP) regimen showed similar efficacy in treating adult Langerhans cell histiocytosis, with non-active disease rates of approximately 70% for both groups.

However, the CEVP regimen was associated with a significantly higher rate of neutropenia (48.4%) compared to the VP regimen (7.1%), indicating a potential safety concern with the more intensive treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of vindesine and prednisone and cyclophosphamide, etoposide, vindesine, and prednisone as first-line treatment for adult Langerhans cell histiocytosis: A single-center retrospective study. Duan, MH., Han, X., Li, J., et al.[2016]

In a study of seven male patients with multisystem or multifocal Langerhans cell histiocytosis, cladribine treatment led to clinically significant responses in all patients, with 86% achieving durable complete remissions over a median follow-up of 37 months.

Cladribine demonstrated a favorable safety profile, with the most common side effects being transient bone marrow suppression, including grade 3 lymphopenia in 71% of patients, indicating it is a viable frontline therapy for this rare condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cladribine (2-chlorodeoxyadenosine) in frontline chemotherapy for adult Langerhans cell histiocytosis: A single-center study of seven cases. Adam, Z., Szturz, P., Vaníček, J., et al.[2013]

In a clinical trial involving 106 newly diagnosed patients with Langerhans cell histiocytosis (LCH), rapid initiation and prolonged chemotherapy led to high rates of complete disease resolution (89% in group A, 91% in group B, and 67% in group C) within a median of 4 months, regardless of disease severity.

The treatment strategy resulted in a low recurrence rate (12% in group A, 23% in group B, and 42% in group C) and no malignancies developed during a median follow-up of nearly 7 years, supporting the efficacy and safety of early and sustained chemotherapy for LCH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment strategy for disseminated Langerhans cell histiocytosis. DAL HX-83 Study Group. Gadner, H., Heitger, A., Grois, N., et al.[2022]

In an international trial involving 193 patients with multisystem Langerhans cell histiocytosis (MS-LCH), intensified treatment with etoposide significantly improved rapid response rates and reduced mortality in patients with risk organ involvement (RO(+)).

Patients younger than 2 years without risk organ involvement (RO(-)) had a remarkable 100% survival rate and over 80% rapid response, highlighting the importance of age and organ involvement in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Gadner, H., Grois, N., Pötschger, U., et al.[2022]

In a phase 2 study involving 27 patients with refractory Langerhans cell histiocytosis, the combination of cladribine and cytarabine resulted in a high overall response rate of 92%, with significant reductions in disease activity scores after treatment.

Despite its efficacy, the treatment was associated with severe toxicity, including grade 4 hematologic toxicity and a 5-year survival rate of 85%, highlighting the need for careful monitoring and management of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cladribine and cytarabine in refractory multisystem Langerhans cell histiocytosis: results of an international phase 2 study. Donadieu, J., Bernard, F., van Noesel, M., et al.[2022]

In a study of 10 children with refractory Langerhans cell histiocytosis, treatment with 2-chlorodeoxyadenosine (2-CdA) and cytosine arabinoside (Ara-C) led to a decrease in disease activity in 6 out of 7 patients who completed at least two courses, indicating significant efficacy.

However, the treatment was associated with severe adverse effects, including WHO grade 4 hematological toxicity in all patients and two septic deaths shortly after the first course, highlighting the need for careful monitoring and consideration of risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-centre pilot study of 2-chlorodeoxyadenosine and cytosine arabinoside combined chemotherapy in refractory Langerhans cell histiocytosis with haematological dysfunction. Bernard, F., Thomas, C., Bertrand, Y., et al.[2013]

In a study of 17 children with refractory Langerhans cell histiocytosis (LCH), the intermediate-dose cytarabine (Ara-c) regimen demonstrated high efficacy, with all patients achieving active disease-better status after treatment, and a 5-year overall survival rate of 100%.

Both treatment regimens (Ara-c alone and Ara-c combined with cladribine) were found to be safe, although higher rates of severe myelosuppression were observed in the combination group, indicating that while effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of intermediate-dose cytarabine in the treatment of children with refractory high risk Langerhans cell histiocytosis]. Wang, WQ., Ge, J., Ma, HH., et al.[2023]

In a study involving over 400 patients with multisystem LCH, prolonged treatment led to significantly improved 5-year survival rates (84%) and lower reactivation rates (27%) compared to previous trials, indicating a more effective approach for high-risk patients.

For low-risk patients, extending treatment duration from 6 to 12 months resulted in significantly lower reactivation rates (37% vs. 54%), suggesting that longer treatment can enhance outcomes for this group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Gadner, H., Minkov, M., Grois, N., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Drug therapy for the treatment of Langerhans cell histiocytosis. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Comparison of vindesine and prednisone and cyclophosphamide, etoposide, vindesine, and prednisone as first-line treatment for adult Langerhans cell histiocytosis: A single-center retrospective study. [2016]

3. England pubmed.ncbi.nlm.nih.gov

Cladribine (2-chlorodeoxyadenosine) in frontline chemotherapy for adult Langerhans cell histiocytosis: A single-center study of seven cases. [2013]

4. United States pubmed.ncbi.nlm.nih.gov

Treatment strategy for disseminated Langerhans cell histiocytosis. DAL HX-83 Study Group. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Cladribine and cytarabine in refractory multisystem Langerhans cell histiocytosis: results of an international phase 2 study. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Multi-centre pilot study of 2-chlorodeoxyadenosine and cytosine arabinoside combined chemotherapy in refractory Langerhans cell histiocytosis with haematological dysfunction. [2013]

8. China pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of intermediate-dose cytarabine in the treatment of children with refractory high risk Langerhans cell histiocytosis]. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. [2022]