After a study period of five years and 5 months, 1045 patients were enrolled onto the study by August 30, 2007. 489 patients were multisystem patients. 255 (52%) patients were RISK patients, and 234 (48%) patients were LOW RISK patients. 556 patients were single system patients, 221 of those were Multifocal bone patients and 171 patients had “Special site” (craniofacial bones or vertebra with soft tissue mass) involvement. The data for Multifocal bone patients and Special Site patients is still premature. And, continued follow-up data collection and evaluation in all patient groups is required for conclusions to be made regarding the totality of the study’s objectives.

 In their report from September 19, 2007, the Data Safety Monitoring Committee (DMC) concluded:

 (1) for RISK patients: Although the study has not quite met its accrual goal there is no reasonable chance that adding further patients will demonstrate a clinically significant difference between the two regimens. Their recommendation was that randomization of patients be discontinued either through study closure to new patient entry or non-random assignment of all future patients to regimen A, the standard arm, which does not contain Methotrexate. Further randomization will not add to the value of the study.

 (2) For LOW RISK patients: The DMC concluded that further accrual to the randomized study is not needed and further accrual to six months of ongoing therapy cannot be justified. The study should either be closed or low risk patients should non-randomly be placed on 12 months of therapy.

The LCH III Study is closed to new patient entry in North America in all three groups as of February 6, 2008. All patients already enrolled on the study should continue treatment as previously randomized and should be followed thoroughly to allow full secondary endpoint data collection. 

The opening of the LCH IV Study is planned for the beginning of 2009.

HLH STUDY GROUP REPORT
Submitted by Jan-Inge Henter, Chairperson

The HLH Study Group is mainly aiming at improving diagnosis and treatment for patients suffering from FHL/HLH. We also want to improve knowledge on the biological mechanisms causing the disease. The HLH-94 treatment protocol has been a therapeutic success. It also provided a lot of research data. There are defects in three genes known to cause FHL; perforin, Munc13-4 and syntaxin-11.

HLH-94: The HLH-94 protocol was closed for new patients by Dec 31, 2003, but is open for further reports of patients that initiated their HLH-94-therapy prior to that date. The protocol has been effective and appreciated. Most patients registered are from Europe and Japan. The outcome of the patients recruited the first four years is around 50% (around 75% survive until BMT, and around 65% survive the BMT) as published in Blood 2002; 100:2367-2373.

CNS disease: A detailed analysis has been performed by Dr Horne on 193 patients in the HLH-94 data-base with data on neurological symptoms and cerebrospinal fluid at onset (Br J Haematol 2007; E-Publ). At diagnosis, neurological symptoms were reported in 72/193 (37%), abnormal CSF in 101/193 (52%), and either or in 122/193 (63%). Altogether 16/107 (15%) survivors had neurological sequelae at follow-up (median 5.3 years). Children with abnormal CSF also have increased risk of neurological sequelae. It is suggested that prompt treatment of HLH at onset or relapse may reduce these complications.

HLH-2004: The present study HLH-2004 was opened Jan 1, 2004. There are only minor alterations in the treatment regimen as compared to HLH-94; one important change is that cyclosporin A is initiated at onset of therapy instead of after 8 weeks. In addition to the treatment protocol itself, biological studies on genetics and cytotoxicity will be associated with the protocol. In addition to the study subcenters (Scandinavia, Germany, Benelux, United Kingdom, Italy, USA and Japan), local coordinators for Spain, Austria and South America are associated with the new protocol. We hope the results will be even better than the HLH-94 results, but it is still too early to draw any conclusions on the outcome of this treatment protocol. The protocol is published in Pediatric Blood Cancer 2007; 48:124-31. 

LCH CNS STUDY GROUP REPORT
Submitted by Nicole Grois, Chairperson

In the LCH CNS study 144 patients with neuro-degeneration are registered. However, only 35 patients are evaluated with neurological test, 31 with psychological evaluations and only 20 with brain stem evoked potentials. Only 9 patients have follow up evaluations.

From the 1262 patients registered in the LCH III study, 43 patients were reported to have neuro-degeneration on MRI (39 for the GPOH, 3 from Scandinavia and 1 from France). Only a minority of these patients have been evaluated according to the guidelines as given in the protocol.

The study group concluded that it is essential that all CNS patients who receive any kind of therapeutic intervention be evaluated according a uniform diagnostic and follow up program, preferably including CSF studies as recommended by Jan-Inge Henter, to assess the course of the disease and any eventual response to therapy. The group will conclude on and disseminate such a program.

LCH-HCT STUDY GROUP REPORT
Submitted by K. Scott Baker, Chairperson

This is a new transplant protocol for patients with refractory/resistant LCH, “Reduced Intensity Hematopoietic Cell Transplantation for Patients with Resistant Langerhans Cell Histiocytosis”. The hypothesis of this trial is that allogeneic hematopoietic cell transplant can salvage high risk LCH patients refractory to available chemotherapy approaches and that the reduced intensity conditioning (RIC) regimen will allow HCT in heavily pretreated patients with acceptable transplant related mortality. The primary objective of the trial will be to determine the overall and disease free survival at 1 and 3 years after reduced intensity HCT in poor risk patients with LCH. 

Eligibility for the trial will be patients with multisystem LCH who have involvement of one or more "risk" organs and progressive disease after treatment with the LCH-III protocol or other standard LCH directed therapies, and who have failed after at least one cycle of the current salvage protocol (LCH-S 2005) or similar therapy. 

The protocol was finalized at the Histiocyte Society’s Annual Meeting in Cambridge (September 2007) and subsequently submitted to the Society’s Scientific Review Committee (SRC) and the HS Executive Board for final approval. The SRC and Board gave final approval and the protocol was distributed to all HS members in mid October. 

SALVAGE STUDY GROUP REPORT
Submitted by Jean Donadieu, Chairperson

Until recently the prognosis of patients suffering with systemic LCH, especially with hematological dysfunction AND refractory to the standard first line therapy (i.e. vinblastine and steroid) was extremely poor, with no more than 30% of survival expected.

In 2005, the French LCH Study Group reported that a pilot study (Bernard, F et al, Eur J Cancer 2005) had reported a better outcome in a tiny group of 10 patients treated by the association 2 cda and Ara C; seven long term survivors were observed while 2 patients died from early toxicities, and one died after a early switch to bone marrow transplant.

Because of the known, extremely poor outcome of this group of patients, and in lack of other convincing literature, the therapeutic approach of this survey was considered as a potential, useful therapeutic approach. In April 2004, a Salvage Committee was constituted in the Histiocyte Society, who decided to assess the interest of this protocol a larger scale. 

The protocol was designed as a phase II open labeled protocol and an enrollment of about 6 to 10 new cases a year were expected world wide, underlying the extreme rarity of the diseases. The first interim analysis has been planned after the inclusion of the first 13 patients, and the final analysis after 30 patients. By Sept 21, 2007, the protocol was officially open in France, Canada, Italy and a few centers in the United States.

ADULT STUDY GROUP REPORT
Submitted by Maurizio Aricò and Abdellatif Tazi

The Adult Study Group met in the HS meeting venue on September 23, 2007, at 8.00 a.m. It was attended by the following: M. Aricò (Italy, chair), A. Tazi (France, co-chair), J. Fichter (Germany), D. Kauschka (Germany), K. McClain (USA), Prof. Doberauer (Germany).

It was discussed that the treatment-related toxicity may be considered by some groups as a limiting factor. After a wide discussion, it was agreed that the study will be “amended”, with the following modifications:

The study will focus only on patients with MS disease, more likely to need chemotherapy in the opinion of most participants. Thus the “Multifocal bone/ special sites” will be closed.

Initial therapy will be modified. To reduce intensity, VBL will be administered at the same dose but only every other week (1, 3, 5) during the first 6 weeks. Steroid dose can also be reconsidered.

Information on toxicity will be intensively required for the patients enrolled in the study to answer the question about compliance and toxicity.

The list of amendments will be circulated to al the Study Group members for a wider discussion in the participating countries, aiming at maximizing the compliance of the physicians and thus patient accrual.

Furthermore, involvement of adult specialists will be intensively pursued in all the involved countries. Chairmanship of the trial and of the study group should be given to adult specialists as soon as possible. 

A. Tazi illustrated the current status of the “pulmonary isolated disease” arm of the study LCH-A1, which he chairs. He remarked that this study is aimed at describing the natural course of the disease and also to evaluate the impact of steroid monotherapy.