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Video Recorded Presentations from the
National Conference on Histiocytic Disorders 2007

Project Funding Update

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Date of Award: December 2007

Amount of Award: $50,000

Title of Awarded Project: Mechanisms of IL-17A-dependent dendritic cell long-term survival and fusion in Langerhans cell histiocytosis

Principal Investigator(s): Christine Delprat, MD, PhD

Institution of Awarded Project: INSERM Lyon, France

Layperson Summary: Langerhans cell histiocytosis (LCH) may affect any age group, from the newborn to the elderly, but clinical features, pathogenesis, and treatment outcome derives from the paediatric experience. The incidence for LCH of around 1:200,000 children per year, peaks at 1?3 years. LCH is an ?orphan? disease that belongs to the Histiocytoses. The course of LCH is often unpredictable, varying from spontaneous regression and resolution to rapid progression and death or repeated recurrence and recrudescence with a considerable risk of permanent sequelae since tumors destroy the tissue where they grow: bone in 80% of patients with multisystem disease, but also soft tissues and occasionally central nervous system involvement. We have just demonstrated that inside lesions, dendritic cells (DC) and multinucleated giant cells (MGC) produce IL-17A, a messenger of the human immune system which has a dominant role in the development and maintenance of several chronic inflammations, such as Mycobacterium infection, Crohn's disease, rheumatoid arthritis and multiple sclerosis. Thus, LCH belongs to IL-17A-related disease family. Moreover, we have just discovered a novel IL-17A-dependent pathway of DC fusion which probably gives rise to MGC observed in LCH lesions. Our objective is to discover the mechanisms of DC long-term survival induced by IL-17A and required for DC fusion in order to design therapeutic agents able to prevent DC survival and their subsequent fusion and differentiation into aggressive tissue-destructive MGC. These therapeutic agents may abrogate or at least reduce tissue destruction in all LCH lesions.

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Date of Award: December 2007

Amount of Award: $50,000

Title of Awarded Project: Biomarker monitoring of CNS disease in LCH

Principal Investigator(s): Jan-Inge Henter, MD, PhD

Institution of Awarded Project: Karolinska Institutet Stockholm, Sweden

Layperson Summary: Problem formulation: Langerhans cell histiocytosis (LCH) is a disease of unknown cause and a remarkably variable clinical course. It may present as a discrete or intense rash, or as one or multiple lytic bone lesions that may resolve spontaneously, but it may also develop into a potentially lethal disease involving specific risk organs, defined as the lungs, liver, spleen and the hematopoietic system. During recent years it has become obvious that the risk of developing late sequelae is one main concern in LCH, and it may affect as many as 40-60% of all survivors. One major concern is the risk of developing progressive degeneration of the brain, often referred to as Central Nervous System-LCH (CNS-LCH). The CNS may be affected already at the diagnosis of LCH, then most commonly involving the hormonal function that may result in diabetes insipidus, growth hormone deficiency and sometimes also more extended hormone deficiences. Of particular concern is the development of cerebral dysfunctions, and clinical CNS complications has been reported to affect at least 10% of all LCH patients. Notably, these CNS complications can be both pronounced and severe, and result in severe neuromotor deficiencies, behavioral disturbances, as well as severe cognitive dysfunctions and death. It is also alarming that this neurodegeneration appear to be progressive, and neurological sequelae may appear as late as 20 years after the initial diagnosis. Imaging with Magnetic Resonance Imaging (MRI) is today considered the best way to diagnose neurodegeneration in LCH.

Obviously, there is a desire to reduce the clinical development of CNS-LCH. However, in order to evaluate potential therapies there is a need to be able to monitor the disease course in the CNS, and since the clinical deterioration and the development of radiological findings are slow processes, it is presently difficult to evaluate the effects of various therapeutic attempts. Therefore, it would be beneficial to be able to evaluate present, ongoing CNS disease activity.

Specific Aim: To identify and evaluate biomarkers of present, ongoing CNS-LCH activity.

Work proposed: In a cohort of patients with MRI-verified CNS-LCH, we perform lumbar puncture (a clinical routine procedure) in order to obtain cerebrospinal fluid (CSF) samples. We analyze these CSF samples to evaluate the potential value of CSF biomarkers used to evaluate other neurodegenerative disorders. These markers are called glial fibrillary acid protein (GFAp), neurofilament protein, light chain (NF-L), and total tau protein. We then aim to correlate these CSF biomarker levels with clinical and neuroradiological findings.

Preliminary data: We have evaluated NF-L, tau and GFAp levels in a set of CNS-LCH patients and noticed that all these children had elevated levels of at least one of these markers. Notably, the patient with the most severe clinical and neuroradiological CNS-LCH also displayed the highest levels of NF-L and GFAp. Similarly, three patients with non-active disease at the time of evaluation had low tau levels and normal or only slightly elevated NF-L. Moreover, the tau levels also correlated with the systemic disease activity.

Significance: Interestingly, our data indicate that these biomarkers for neurodegeneration are elevated in patients with CNS-LCH. Therefore, these markers may be used to detect CNS-LCH in an early phase of the disease, and to monitor the disease development. Moreover, with the availibility of CSF biomarkers, it may be possible to more promptly detect positive and negative effects of various treatment attempts for CNS-LCH. Ultimately, it is our hope that the use of CSF biomarkers may facilitate the development of clinically useful treatments for this potentially devastating condition.

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The Histiocytosis Association of Canada supports a half time clinical research associate (CRA) at the Hospital for Sick Children, Toronto

This support is essential as it allows the enrollment of Canadian patients onto the International Histiocyte Society studies as well as important research at Sickkids hospital.

The currently open Histiocyte Society studies are LCH-III and HLH-2004.

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Sickkids acts as the Canadian sponsor for these studies and the CRA is responsible for the conduct of the studies, not only at Sickkids but at all the centers that have opened the studies. Without her help, none of this would be possible.

Sickkids also does it‘s own Histiocytosis research studies with the help of the CRA. The results of these studies are presented at Medical meetings and published in major pediatric journals.

A list or recent publications from the Sickkids group are:

Breakey VR, Abla O, Weitzman S, Abdelhaleem M: Hemophagocytic Lymphohistiocytosis Onset during Induction Therapy for Precursor B-cell Acute Lymphoblastic Leukemia. Journal of Pediatric Hematology/Oncology. 2008 ( In press)

Gupta, A, Weitzman S, Abdelhaleem M. The role of Hemophagocytosis in Bone Marrow Aspirates in the Diagnosis of Hemophagocytic Lymphohistiocytosis. Pediatric Blood and Cancer 2008: 54: 194-197. Invited Editorial.commentary

Gupta A, Tyrrell P, Valani R, Benselar S, Weitzman S, Abdelhaleem M. The role of the initial bone marrow aspirate in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatric Blood and Cancer 2008 (in press)

Lau LM, Stuurman K, Weitzman S. Skeletal Langerhans cell histiocytosis in children: permanent consequences and health-related quality of life in long-term survivors. Pediatric Blood Cancer 2008: Mar: 50(3): 607-12.

Gupta A, Tyrrell P, Valani R, Benselar S, Abdelhaleem M, Weitzman S. Diagnosis, Treatment Decisions and Outcome in patients with Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome. Journal of Hematology/Oncology 2008 (in press)

Abdelhaleem M, Shago M., Beimnet K., Sayeh E., Bartakke S., Weitzman S. Childhood acute myeloid leukemia with hemophagocytosis by the blasts and inv(8)(p11q13) with MOZ- TIF2fusion transcripts. Journal of Pediatric Hematology & Oncology 2007 Sep;29(9):643-5.

Lau L, Krafchik B, Trebo M, Weitzman S: Cutaneous Langerhans Cell Histiocytosis of the Skin in Children under One Year. Pediatric Blood and Cancer 2006: 46(1): pp 66-71

Weitzman S, Jaffe R: Uncommon Histiocytic Disorders: The Non-Langerhans Cell Histiocytoses. Pediatric Blood and Cancer 2005: 45(3): pp 256-64.

Weitzman S, Pritchard J: Getting there? Salvage Therapy for Refractory Langerhans Cell Histiocytosis in Children. European Journal of Cancer 2005: 41(17): pp 2592-4. Invited Editorial

Odame I, Li P, Lau L, Dodo W, Noteworthy M, Babyn P, Weitzman S: Pulmonary Langerhans cell histiocytosis: a variable disease in childhood Pediatric Blood and Cancer 2005: 47(7): pp 889-93.

The Sickkids Division of Haematology /Oncology has just opened a new LCH study in cooperation with the Department of Radiology at the hospital. This study will review X-rays and MRI scans of all bone lesions in LCH patients diagnosed and treated at the Hospital for Sick Children from 1995-2005. The aim of the study is to see if there are any radiologic features that can predict the outcome.. The investigators are particularly interested in seeing if they can find X-ray features that can predict recurrences as well as progression to diabetes insipidus and CNS disease and other permanent problems. If such features could be found, then the therapy could be changed early to try to prevent these potentially serious permanent problems.

The Histiocyte Society studies are :

LCH III – Third Treatment Protocol of the Third International Study for Langerhans Cell Histiocytosis

Overall Study Goals:

• Deliver risk-specific therapy depending on the extent and severity of the disease at diagnosis
• Evaluate the patient’s response to treatment in the different patient populations
• Evaluate how many patients to not respond to therapy or experience a reactivation of their disease during treatment
• To assess morbidity, being therapy toxicities and what the permanent consequences of these toxicities are in the different patient populations

Overall Study Design:
Multi-system risk patients: Patients are randomly assigned to one of two treatment arms. The overall goal is to reduce mortality and morbidity in this patient population by comparing the responses and rate of reactivation of the treatment in two different arms.

Multi-system low risk patients: Patients are randomly assigned to receive 6 or 12 months of continuation therapy to understand the value of prolonged treatment in this patient population. To determine if adding a second course of initial (more intense) treatment for patients that do not exhibit a sufficient response will have an increased response rate.

Single system Multifocal bone and Localized Special Site patients: Patients will all follow one arm of treatment to determine the rate of reactivation and permanent consequences in comparison to patient populations of earlier studies.

Canadian Involvement
The Hospital for Sick Children is the acting Canadian lead site for this study. There are a total of 6 centres across Canada that have contributed to this study by enrolling patients and continuing to submit treatment and follow up data on these registered patients.

With the support of the Canadian centres as well as numerous other international centres, the LCH III study has successfully met patient goals and is currently closed to enrollment. Data is currently being reviewed and the next front-line study for LCH patients is in development.

HLH 2004 – Hemophagocytic Lymphohistiocytosis Study Group, Treatment Protocol of the Second International HLH Study 2004

Overall Study Goals:

• To evaluate a revised (from HLH-94) treatment plan, with the goal to initiate and maintain an acceptable condition so that curative stem cell transplant can be performed in patients with familial, relapsing or severe HLH
• To evaluate and improve the results of stem cell transplant with various types of donors and to evaluate the importance of the patient’s remission status at the time of transplant
• To evaluate the neurological long-term complications
• To gain an improved understanding of the cause of the disease through biology studies

Overall Study Design:

The overall study for HLH-2004 classifies patients into separate populations based upon their familiar status as well as their response following the first 8 weeks of therapy:

1. genetically verified or familial disease
2. persistent non-familial, non-genetically verified disease
3. resolved non-familial, non-genetically verified disease

This study does not involve randomization, instead patient classification determines further treatment.

Canadian Involvement
The Hospital for Sick Children & Dr Sheila Weitzman acts as the Canadian sponsors for HLH-2004. To date, 4 Canadian centres have contributed to this study through patient enrollment. This study is currently ongoing and is currently open to further patient recruitment.

None of this work would be possible without the support of the Histiocytosis Association of Canada