Combination Therapy for Langerhans Cell Histiocytosis

Recruiting at 43 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks to identify the best treatment options for children with Langerhans Cell Histiocytosis (LCH), a rare disease that causes excessive immune cells to accumulate and form tumors. It tests various drug combinations, including Cytosine Arabinoside (a chemotherapy drug), to determine which are most effective for children with different LCH conditions, particularly those affecting vital organs or the brain. Participants must be under 18 and have a confirmed LCH diagnosis, especially if previous treatments have failed. As a Phase 2, Phase 3 trial, this research evaluates the treatment's effectiveness in an initial group and represents the final step before FDA approval, offering hope for effective new therapies.

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 there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that a combination of 2-chlorodeoxyadenosine (2-CdA) and cytosine arabinoside (Ara-C) can treat challenging cases of Langerhans Cell Histiocytosis (LCH) in children. Some studies suggest this mix works well for severe LCH unresponsive to other treatments. However, like many potent treatments, it may have side effects, so discussing these with a doctor is important.

Using prednisone and vinblastine together is a common approach for LCH. Studies indicate that most patients generally tolerate this combination well, and it is often the first treatment doctors try.

The drugs mercaptopurine and methotrexate also treat LCH and other conditions. They can help manage the disease and are generally considered safe, but side effects may occur, so regular check-ups with healthcare professionals are important.

Indomethacin treats bone LCH and has proven effective in both children and adults. It is a well-known medicine often used for its ability to reduce inflammation.

Hematopoietic stem cell transplantation (HSCT) serves as a more intensive treatment for severe cases that don't respond to other therapies. While it offers hope, it involves significant medical procedures and carries risks.

Intravenous immunoglobulin (IVIG) is under study as a treatment to slow the progression of neurodegenerative LCH. It is used in some other conditions and is generally considered safe.

Overall, these treatments have shown varying levels of safety and effectiveness. Consulting with healthcare providers can help weigh the benefits and risks for each specific case. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Langerhans Cell Histiocytosis (LCH) because they offer diverse strategies tailored to patient needs. Unlike standard treatments such as Prednisone and Vinblastine, which are first-line options, the trial explores combinations like Cytosine Arabinoside and 2-chlorodeoxyadenosine for patients with risk organ involvement. This approach targets those who don’t respond to initial therapies, potentially addressing more complex cases. Additionally, for isolated tumorous or neurodegenerative CNS-LCH, the trial investigates the use of monotherapy with Ara-C or intravenous immunoglobulin, offering new hope for those with limited current options. The trial also examines reduced intensity conditioning for hematopoietic stem cell transplantation, aiming to improve survival rates for patients who need more intensive interventions.

What evidence suggests that this trial's treatments could be effective for Langerhans Cell Histiocytosis?

Research has shown that a combination of two drugs, 2-chlorodeoxyadenosine and Ara-C, effectively treats children with hard-to-treat Langerhans Cell Histiocytosis (LCH). In this trial, participants in Stratum III will receive this combination as a salvage treatment for risk LCH. The combination of prednisone and vinblastine, used in Stratum I, serves as a common first treatment, improving survival rates and reducing disease recurrence in cases affecting multiple systems. Indomethacin, an option in Stratum II, has effectively treated bone LCH, with many patients remaining disease-free after five years. Using mercaptopurine and methotrexate together, also in Stratum II, has lowered the chances of disease recurrence in multisystem LCH. Finally, hematopoietic stem cell transplantation, offered in Stratum IV, provides hope for those who do not respond well to other treatments, although it carries higher risks. ^{1 2 4 5 6}

Who Is on the 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

Are You a Good Fit for This Trial?

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.

I have newly diagnosed single-system Langerhans Cell Histiocytosis not in my bones, brain, or 'CNS-risk' areas.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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 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 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 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 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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/19125089/

Treatment of refractory Langerhans cell histiocytosis (LCH ... The combination of 2-chlorodeoxyadenosine (2-CDA) and cytosine arabinoside (Ara-C) has been shown to be effective in children with refractory Langerhans cell ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/16291085/

Multi-centre pilot study of 2-chlorodeoxyadenosine and ... We conclude that 2-CdA and Ara-C combined chemotherapy probably has major activity in childhood refractory Langerhans cell histiocytosis.

3. texaschildrens.org texaschildrens.org/content/news/study-finds-one-treatment-stands-above-others-adults-langerhans-cell-histiocytosis

Study finds one treatment stands above others for adults ... "Cytarabine (cytosine arabinoside) is clearly the winner here - it's the most effective and least toxic," said Dr. Ken McClain, professor of pediatrics - ...

4. cell.com cell.com/cms/10.1016/j.heliyon.2023.e19277/attachment/05aa4a5c-1b27-4490-bc98-617e60cbf05b/mmc1.docx

Cladribine and cytarabine in children refractory high risk ... The intermediate-dose regimen of 2CDA and Ara-c had a higher event-free survival rate and a similar overall survival rate compared with the low-dose regimen.

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0959804905001541

Multi-centre pilot study of 2-chlorodeoxyadenosine and ... The aim of this study was to assess the efficacy and adverse effects of 2-chlorodeoxyadenosine (2-CdA) and cytosine arabinoside (Ara-C) in children with ...

6. ashpublications.org ashpublications.org/blood/article/126/12/1415/34387/Cladribine-and-cytarabine-in-refractory

Cladribine and cytarabine in refractory multisystem ... Patients with LCH, risk organs, refractory to standard VBL-steroid regimen have a poor survival, ∼30%. In a phase 2 study, with 5 years' ...