Blood and Lymph Conditions

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Neoplasms

Rare Diseases

Erdheim-Chester Disease

Histiocytosis, Langerhans-Cell

Histiocytosis

Histiocytosis, Sinus

Sarcoma

Histiocytic Sarcoma

Lymphatic Diseases

Lung Diseases

Lung Diseases, Interstitial

Respiratory Tract Diseases

Histiocytosis, Non-Langerhans-Cell

Histiocytic Disorders, Malignant

Neoplasms by Histologic Type

Lipogranulomatosis

Langerhans Cell Histiocytosis

Rosai-Dorfman Disease

Polymorphic Reticulosis

Soft Tissue Sarcoma

Non-Langerhans-Cell Histiocytosis

Gaurav Goyal, MD

The purpose of the study is to describe the burden of chronic health conditions, psychological dysfunction, chronic pain, healthcare utilization, worse health-related quality of life, overall mortality, and cause-specific mortality among individuals with histiocytic disorders

Background

Over the last decade, major advances have occurred in histiocytic disorders with the discovery of MAPK-ERK pathway mutations leading to targeted therapeutics using BRAF- and MEK-inhibitors. However, there is a lack of large studies informing the burden of morbidity and mortality among people with histiocytosis. Institutional studies in pediatric LCH suggest that survivors suffer from long-term impairment of health related quality of life, cognitive dysfunction, pituitary dysfunction, and hearing difficulties in 20-50% cases. Studies from the investigative team and others have also shown a high incidence of acute myeloid leukemia and other second primary malignancies in pediatric and adult LCH. Chronic medical conditions may arise as a function of the disease biology or due to cancer therapy, as seen in other hematologic malignancies.

Design

Retrospective cohort study aimed at determining the risk of chronic health conditions and cause-specific mortality in pediatric and adult patients with histiocytic disorders. The study will include patients from the Histiocytosis Association registry and other institutions including UAB (n\~6000). The participants will complete a validated questionnaire capturing details of chronic health conditions, health related quality of life, cognitive/psychological function, and healthcare utilization.

Future directions

The results from our study will be instrumental in formulating follow-up guidelines for histiocytic disorders and developing targeted survivorship programs to improve overall outcomes.

Histiocytic Disorder Follow-up Study

The CTCAE criteria for CHCs distinguishes each acute and chronic condition (including SPMs) in persons with cancer from grades 1 through 4 with unique clinical descriptions of severity (grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, life-threatening/disabling). The main outcome will be the number of distinct CTCAE grade 3-4 conditions among LCH cases compared with unaffected (non-cancer) controls.

Causes of death will be grouped into primary cancer (LCH)-related mortality (PCRM) and non-primary cancer-related mortality (NPCRM - death from all causes other than the index LCH diagnosis) by two independent investigators.

We will build a prediction model that has a good discrimination for predicting CHC, SPMs, and psychological outcomes separately using data from the LCH (case) cohort.

University of Alabama at Birmingham

Principal Investigator

Nervous System Diseases

Skin and Connective Tissue Diseases

Neurodegenerative Diseases

Xanthogranuloma, Juvenile

Skin Diseases

Children (≥ 6 months) and young adults (\<21 years) with recurrent active LCH lesions (may also have LCH-ND).

Patients of any age (≥ 6 months) with progressive LCH Neurodegenerative Disease (LCH-ND) without other sites of active LCH.

Newly diagnosed or relapsed/refractory children (≥ 6 months) and young adults (\<21 years) with other histiocytic disorders including juvenile xanthogranuloma, Erdheim-Chester disease, histiocytic sarcoma and Rosai-Dorfman disease.

Adults (≥21 years) with LCH or other histiocytic disorder with recurrent active lesions (may also have LCH-ND).

All groups will receive the same intervention. Cobimetinib will be given orally at a maximum dose of 60mg daily for 21 days on, then 7 days off, in a 28-day treatment cycle for a total of 12 cycles (approximately 12 months).

Cobimetinib

Carl E Allen, MD, PhD

Olive Eckstein, MD

Michael Henry, MD

Lilbeth Torno, MD

Birte Wistinghausen, MD

Elias T Zambidis, MD PhD

Barbara Degar, MD

Sara Galinko

Sara Clyburn

Heidi Clough

Erin Butler, MD

Carl E. Allen, MD, PhD

Diane Puccetti, MD

This is a research study of a drug called cobimetinib in children and adults diagnosed with Langerhans cell histiocytosis (LCH), and other histiocytic disorders that has returned or does not respond to treatment. Cobimetinib blocks activation of a protein called Mitogen-activated protein kinase (MEK) that is part of incorrect growth signals in histiocytosis cells. Four different groups of patients will be enrolled.

Histiocytic disorders are diseases caused by misfunctioning or buildup of particular immune cells called histiocytes. Many histiocytic disorders (LCH, juvenile xanthogranuloma (JXG), Erdheim-Chester disease (ECD), and Rosai-Dorfman Disease (RDD)) arises from blood cells that receive incorrect growth signals. These incorrect signals are caused by changes in genes (mutations) that lead to tissue damage (lesions) which causes disease. Some patients with LCH can develop neurodegeneration (LCH-ND) which is damage to neurons that results in reduced brain function, from LCH cells that go to the brain and activate inflammation. LCH arises from blood cells that receive incorrect growth signals. These incorrect signals are caused by mutations (changes in genes). The LCH blood cells can create changes in the structure of almost any organ, and can cause damage to normal organ function.

The purpose of this research study is to learn whether cobimetinib is safe and effective in subjects diagnosed with LCH, LCH-ND, RDD, JXG and ECD which may have a specfic mutation called BRAF-V600E. In healthy cells, certain proteins (called BRAF and MEK) are thought to help control normal cell growth. BRAF-V600E is a specific change in a gene that may cause cancer cells to grow and spread by sending constant signals to the MEK protein. Cobimetinib is designed to attach to and block the activity of MEK.

Participants are assigned to one of 4 groups in parallel for the duration of the study. All 4 groups receive the same intervention.

Cobimetinib in Refractory Langerhans Cell Histiocytosis (LCH), and Other Histiocytic Disorders

A Phase 2 Study to Assess the Safety and Efficacy of Cobimetinib in Refractory Langerhans Cell Histiocytosis, LCH-Associated Neurodegenerative Disease, and Other Histiocytic Disorders.

Response assessment using modified RECIST criteria for target lesions with specific mutations (e.g. BRAF-V600E) . Best response rate by 1 year of therapy.

Proportion of participants with (complete response, partial response, stable disease, progressive disease) by 1 year of therapy with Cobimetinib.

It is assumed that at each protocol-specified timepoint, a response assessment occurs. Status calculation will occur at each timepoint for patients who have measurable disease at baseline per the criteria defined in the protocol.

Progression Free Survival defined as the length of time during and after the treatment of a disease, that a patient lives with the disease but it does not get worse.

Assessment of the nature and severity of adverse events in patients treated with Cobimetinib for histiocytic disorders.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Histiocytic Disorder Follow-up Study	NCT05915208	Histiocytosis Langerhans Cell... Erdheim-Chester... Rosai Dorfman D... Xanthogranuloma Malignant Histi...		18 Years - 89 Years	University of Alabama at Birmingham
Cobimetinib in Refractory Langerhans Cell Histiocytosis (LCH), and Other Histiocytic Disorders	NCT04079179	Langerhan's Cel... Juvenile Xantho... Erdheim-Chester... Rosai Dorfman D... Neuro-Degenerat... Histiocytic Sar... Histiocytic Dis...	Cobimetinib	-	Baylor College of Medicine

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