the langerhans cell histiocytosis salvage therapy … · langerhans cell histiocytosis (lch) ......

LCH-S-2005

An International Phase II Study

evaluating the combination of

Cladribine (2 CdA) + Cytarabine Cytosine-

arabinoside in refractory Multisystem

Langerhans Cell Histiocytosis (LCH)

The Langerhans Cell histiocytosis

Salvage Therapy Working Group

Histiocyte Society

Date: December 2005

Salvage therapy S 2005 December 2005

Composition of the Working group ..............................................................................................................................3 Background ...................................................................................................................................................................6 Study objective............................................................................................................................................................10 Eligibility criteria ........................................................................................................................................................11

Inclusion criteria:.....................................................................................................................................................11 Exclusion criteria:....................................................................................................................................................11

Endpoints.....................................................................................................................................................................13 Major endpoint: .......................................................................................................................................................13 Secondary endpoints: ..............................................................................................................................................13

Treatment ....................................................................................................................................................................14 Combination chemotherapy: Initial 2 courses (figure 1).........................................................................................14 Decision rules after 2 courses (figure 2): ................................................................................................................14 Maintenance therapy (figure 3) ...............................................................................................................................15

Part 1: ..................................................................................................................................................................15 Part 2: ..................................................................................................................................................................15 Part 3: ..................................................................................................................................................................16 Oral 6-mercapto purine and oral Methotrexate: How to adapt the therapy in case of side effects......................16

Supportive care guidelines ..........................................................................................................................................20 Protocol deviation as a consequence of side effects....................................................................................................22 Pre-treatment evaluation..............................................................................................................................................23 Evaluation and response criteria..................................................................................................................................23 Follow-up and long term outcome ..............................................................................................................................25 Drug Information.........................................................................................................................................................26

Cladribine (2-Cda) (Leustatin)............................................................................................................................26

Cytarabine (Ara-C) (Cytosar-U) .........................................................................................................................27 Expected toxicity.........................................................................................................................................................29

Drug combination....................................................................................................................................................29 Cladribine(2-CDA) (Leustatin)...........................................................................................................................29

Cytarabine (Ara-C) (Cytosar-U) .........................................................................................................................30 Toxicity reporting........................................................................................................................................................31 Statistical considerations .............................................................................................................................................32 Appendix .....................................................................................................................................................................34

Appendix 1 : Risk organs definition........................................................................................................................35 Appendix 2 : WHO toxicity criteria ........................................................................................................................36 Appendix 3: Data monitoring Time table...............................................................................................................42 Appendix 4: Informed consent ................................................................................................................................43 Appendix 5 : LCH 2005 S Inclusion sheet (2 pages) ..............................................................................................44 Appendix 6 : LCH 2005 S Toxicity report sheet in case of severe adverse event OR DEATH ............................46

References ...................................................................................................................................................................47

of 48


Composition of the Working group

Name City Country

M Arico Palermo, Italy

R Arceci Baltimore, USA

F Bernard Montpellier, France

J Braier Buenos Aires, Argentina

J Donadieu –Chair Paris, France

M Egeler Leiden, Netherlands

N Grois Vienna, Austria

J-I Henter – Co Chair Stockholm, Scandinavia

K Mc Clain Houston, Texas

M Minkov Vienna, Austria

J Pritchard Edinburgh, UK

C Rodriguez – Galindo Memphis, USA

K Stine Little Rock, USA

Takamato Kyoto, Japan

S Van Gool Leuven, Belgia

S Weitzman Toronto, Canada

K Windebank Newcastle, UK

J Whitlock Nashville, USA

Composition of the Working group /details:

Study Chairman Jean Donadieu Hospital Trousseau Hematologie-Oncologie 26 Rue Du D Netter Paris, F-75012 France P + 33 - 1- 44736062 F + 33 – 1 - 44736573 e-mail: [email protected]

Maurizio Arico U.O. Onco-Ematologia Pediatrica Ospedale dei Bambini "G. Di Cristina" Via Benedettini 1 90134 Palermo Tel. +39-091-6666131 Fax +39-091-6666001 e-mail: [email protected]

Bob Arceci, Johns Hopkins Oncology Center Bunting-Blaustein Cancer Research Building 1650 Orleans Street 2M51 Baltimore, MD 21231 United States of America P +1 – 410 - 5027519 F +1 – 410 - 9558897

e-mail: [email protected]

Frédéric Bernard Pédiatrie 3, Hémato-Immuno-Oncologie Pédiatrie Hôpital Arnaud de Villeneuve Av. du Doyen Giraud 34000 MONTPELLIER Phone. 33 467336603, Fax.33 467540035


Jorge Braier Pediatric Hemato / Oncology Hospital Garrahan Combate de los Pozos, 1881 Buenos Aires 1245 Argentina P: 54 1 43084300 F 54 11 43085325


of 48

mailto:[email protected]




Maarten Egeler, Leiden University Medical Center Department of Pediatrics - IHOBA, Rm J6-222 PO Box 9600 2300 RC LEIDEN The Netherlands Telephone: 31 71 526-4131/2824 Telefax: 31 71 524-8198


Nicole Grois St. Anna Children's Hospital Kinderspitalgasse 6 A-1090 Vienna, Austria Tel: +43-1-40170-476 Fax: +43-1-40170-430


Jan-Inge Henter, Co Chair Childhood Cancer Research Unit Karolinska Hospital, Q6:05 SE-171 76 Stockholm, Sweden Phone: +46 - 8 5177 2870 or 8- 5177 7098 Telefax: +46 - 8 5177 3184 e-mail: [email protected]

Ken Mc Clain Texas Children’s Clinical care center 6701 Fanin Street Suite 1410 Houston TX 77030 USA P: 1 832 822 4208 F : 1 832-825-1503 e-mail: [email protected]

Milen Minkov St. Anna Children's Hospital Kinderspitalgasse 6 A-1090 Vienna, Austria Tel: +43-1-40170-476 Fax: +43-1-40170-430 e-mail: [email protected]

Jon Pritchard Royal Hospital for sick Children 9 Sciennes Road Department of Oncology & Haematology Edinburgh EH91LF SCOTLAND Phone 44 131 5360000 Fax: 44 131 5360001

e-mail: : [email protected]

Carlos Rodriguez-Galindo, MD Department of Hematology-Oncology St Jude Children's Research Hospital Tel (901) 495-2203 e-mail: [email protected]

Kimo Stine Pediatric Hemato/ Oncology Arkansas children’s Hospital 800 Marshall St. Little Rock AR 72202 USA e-mail: Tel 1 501 364 1494 Fax 1 501 364 3634


Stefaan Van Gool, Pediatric Hemato-oncology and Neuro-oncology University Hospital Gasthuisberg Laboratory of Experimental Immunology Herestraat 49 B-3000 Leuven Belgium Tel: + 32-16-332211 Fax: +32-16-343842


Sheila Weitzman The Hospital for Sick Children 555 University avenue Toronto, Ontario, Canada Tel 416 813 5872 Fax: 416 813 5327


Jim Whitlock Pediatric Hematology/ Oncology Vanderbilt University Medical Center 2220 Pierce Avenue, 397 PRB Nashville, TN 37232-6310 USA Tel 1 615 936 1762 Fax : 1 615 936 1767

e-mail: : [email protected]

Kevin Windebank Senior Lecturer in Child Health, & Consultant Paediatric Oncologist Sir James Spence Institute Royal Victoria Infirmary Newcastle upon Tyne NE1 4LP. UK P 44 191 202 3026 FAX +44 191 202 3060


of 48









The coordinator of the study at the country level is the member of the working group who is responsible for the ethic committee for his country (EU) or for his center (north America). Statistician: Mrs Anne AUPERIN Département d’épidémiologie et Biostatistique Institut Gustave Roussy Rue Camille Desmoulins Villejuif 94800 France e mail : [email protected] Drug Safety Monitoring Board David Webb, UK

Stephan Ladisch USA

MG Valsecchi Italia

of 48


Background

The clinical presentation and outcome of treatment for Langerhans CHcell

histiocytosis (LCH) are is very variable, ranging from an isolated spontaneously

remitting bone lesion to a multi-system disease with life-threatening organ

dysfunction. Dysfunction Involvement of the lungs or of the hematopoetic system

and/or involvement of the spleen, the liver or the digestive tract, are features

which may be associated with a poor outcome (1-6). Since the early 1990’s,

international cooperative approaches to this rare disease have been organized

under the aegis of the Histiocyte Society, an international association of

researchers dedicated to clinical and fundamental research into the histiocytic

disorders. The successive trials have helped to standardize the initial investigations

and have led to the randomized therapy now being tested in the third prospective

therapeutic trial for newly diagnosed patients (LCH III). The trials have also allowed

confirmation of many different prognostic factors, as well as a better understanding

of the natural history of the disease. In patients with multisystem LCH (more than

one organ involved, at the time of diagnosis or during the course of the disease), a

poor response to the initial standard chemotherapy with vinblastine and

corticosteroids prednisolone has been shown to be the most important single

prognostic factor, defining a group of patients with a less than 30% survival rate at

2 years from diagnosis, as detailed in Table 1 (1;3;5;7).

Table 1: Review of the outcome of patients with poor response to therapy

References Study Drugs received in the first 6 weeks

Criteria for definition of failure

Number of resistant patients

Survival rate %

(3;7) DAL HX83

Vinblastine VP16 and corticosteroid

AD Worse 9

11%

(7) DAL HX 90

Vinblastine VP16 and corticosteroid

AD Worse

(1) LCH I Vinblastine or VP16 and corticosteroid

AD Worse 25 40%

(5) French survey

Mainly vinblastine and corticosteroid

Progression of the disease

13 0%

of 48


The progression pattern of the disease is unpredictable, however. The disease

usually retains some sensitivity to treatment but with only partial control followed by

secondary progression. Many of these patients suffer profound and refractory

pancytopenia and usually die from sepsis or bleeding. In this setting, the serum

albumin level is also profoundly decreased, related to digestive tract leak and/or to

lack of production due to liver dysfunction. Both nutritional status and an enhanced

catabolic state contribute to the progressive deterioration.

The clinical presentation of this group of patients differs from those patients with

lung involvement as the sole ‘risk’ organ dysfunction. The outcome in these

patients can also be dramatically compromised as lung destruction can be fatally

aggravated by an undercurrent intercurrent infection or a mechanical complication

such as pneumothorax. These latter situations remain distinct from the

multivisceral involvement previously described, however, and the impact of

chemotherapy is uncertain (8).

Over the last 15 years, several new drugs and or procedures have been reported

as being useful in the treatment of patients with LCH. A new therapeutic approach

is often reported as a promising single case report but unfortunately, further

evaluation in a larger group of patients proves it to be disappointing. This is

especially true for high risk patients with haematological dysfunction and failure to

respond to standard therapy, who represent the majority of early deaths in LCH

(2;4-6). Examples of this are agents such as cyclosporine A, interferon alpha and

2-Chlorodeoxyadenosine (2-CdA) when used as monotherapy (9-18). Despite

promising case reports and small series, stem cell transplantation (SCT) has, as

yet, not been clearly demonstrated to be an effective salvage procedure in this

group of patients. There are many limitations to successful SCT in this setting,

including the difficulty of finding an appropriate donor in a short period of time and

the toxicity of the conditioning regimen. The preliminary results of a small survey of

7 patients transplanted with a low-intensity conditioning regimen, suggests that this

approach may be more promising (20), but this needs to be tested prospectively.

New strategies for the treatment of patients with refractory LCH are therefore much

needed. One promising strategy is a combination of 2-CdA and cytosine

cytarabine-arabinoside (ara-C). To date, only one pilot study using 2-CdA and

Ara-C has been reported (21), which suggests that patients with multivisceral LCH

of 48


and failure of standard therapy may have a favorable response to this therapeutic

stratagem. The main limitation of the study is the small numbers of patients

enrolled, but it is noteworthy that 7 of 10 refractory patients have achieved

sustained complete remission (CR), some with responses evident only after

several months of follow-up (21).This is, a result that is significantly different from

the reported historical outcome for this group of patients.

There is in addition, a good pharmacological rationale for the combination of 2-Cda

and ara-C. 2-CdA is a deoxyadenosine analogue phosphorylated by the enzyme

deoxycytidine kinase (dCK), leading to the formation of 2-CdA mono-, di- and

triphosphate (2-CdAMP, 2-CdADP, and 2-CdATP). These nucleotides are resistant

to deoxyadenosine aminase, and their accumulation results in inhibition of DNA

synthesis and cell death. 2-CdA thus has an antiproliferative effect on histiocytes

and lymphocytes (14). Ara-C Cytosine Arabinoside (Ara-C), a cytostatic drug also

phosphorylated by dCK, has been used successfully, together with vincristine and

prednisolone, as first line treatment of children with disseminated LCH and organ

dysfunction (22). In other studies, both in vitro and in vivo, pretreatment with 2-CdA

resulted in increased accumulation of Ara-CTP (the active form of Ara-C) in

circulating blasts from relapsed adults with refractory acute myelogenous leukemia

(AML) (23). Kornblau et al. also studied the effect of combination 2-CdA and Ara-C

in adults patients with AML(24). Ara-C was administered at a dose of 1 g/m² 2iv

over 2 hours at hour 0, 48, 72, 96 and 120, and 2-CdA at 12 mg/m²/2/day x 5 days

beginning at hour 24. Non-hematopoetic toxicity was generally tolerable. All

patients had a WBC nadir of <0.1 x 109 by day 7, one patient died before day 14

and one patient showed no recovery of platelets beyond 75 days. In general the

myelotoxicity was hard to evaluate in these aleukemic patients because of

confounding factors related to the disease itself.

Evaluation of response is an important issue in the management of patients with

LCH, especially those with multi-organ dysfunction. A recently developed scoring

system (25) has been tested in the evaluation of response to stem cell

transplantation (19) and to the 2-CdA and Ara-C combination (21). This scoring

system takes into account clinical criteria (including fever, spleen and liver size,

oxygen requirement, the number of weekly transfusions and /or the number of

albumin infusions), and a limited number of laboratory parameters (complete blood

of 48


count, albumin level, liver function tests), as well as imaging studies. Further

validation of this scoring system however, will require a prospective, multi-

institutional evaluation and for this present study the established LCH III evaluation

system will be utilized.

of 48


Study objective

To assess the efficacy of the combination of 2-Cda and Ara-C in LCH patients who

fail to respond to front-line chemotherapy AND who have risk organ involvement.

of 48


Eligibility criteria

Inclusion criteria: All the 5 following criteria must be present: a A biopsy-proven definitive diagnosis of LCH

AND

Risk organ involvement (Appendix 1)

AND

Failure of initial therapy defined by disease progression in one or more risk

organs except solely lung(excluding isolated lung involvement), after at least 6

weekly doses of vinblastine and 28 days of corticosteroid prednisolone at a

minimum dose of 40 mg/m2², with or without the addition of a third drug. The

patient will be eligible for inclusion in LCH-S-2005 even if he/she has not been

registered or treated “according to” the LCH-III protocol, however as long as a

similar initial treatment approach is required before inclusion on LCH-S-2005.has

been used. If drugs other than vinblastine and corticosteroid prednisolone have

been given in the two months prior to the inclusion in this study, the coordinator of

the study has to validate the inclusion in writing. Patients who initially respond but

then reactivate with reactivation in a risk organ(s), except solely lung excluding

isolated lung disease, resistant in one or more risk organs after at least 6

weekly doses of vinblastine and 28 days of corticosteroid prednisolone at a

minimum dose of 40 mg/m², 2, may also be enrolled in the study.

AND

Informed consent. All patients or their legal guardians (if the patient is below the

legal age of consent), must sign a research ethics board approved consent form

indicating their awareness of the investigational nature and the risks of this study.

When appropriate, younger patients will be included in all discussions in order to

obtain verbal assent.

Exclusion criteria: The presence of any of the following criteria will exclude the patient from study:

of 48


Isolated sclerosing cholangitis, with an inadequate liver function, as defined by

biological biochemical liver abnormalities and typical imaging, without evidence of

active LCH as the only evidence of risk organ involvement

Isolated lung involvement at any age as well as systemic disease with lung disease as the only risk organ involvement Inadequate renal function as defined by serum creatinine > 3x normal for age.

Pregnancy or breast-feeding.

There is no age limit, but it is important to consider that the 2-Cda Ara-C

association has only been evaluated in young children with LCH until now. Before

inclusion of adult, a contact with the study coordinator is recommended.

of 48


Endpoints

Major endpoint: The major endpoint is the response rate after two courses of therapy,

evaluated at 9-10 weeks from the initiation of the first course therapy.

The response is considered as favorable if the status of the patient is Active

Disease Better or Non Active Disease. Any early death, whatever the cause,

is considered as an unfavorable response.

Secondary endpoints: The number of courses and the time period taken to obtain Non Active Disease.

The time period taken to obtain haematological recovery after each course of

induction therapy. Red cell, neutrophil and platelet recovery will all be analyzed

separately.

The type of subsequent and/or maintenance therapy utilized.

The early and late toxicity.

The early and late morbidity

The early and late mortality.

of 48


Treatment

Combination chemotherapy: Initial 2 courses (figure 1)

Cytosine ArabinosideCytarabine (Ara-C) 500 mg/m2/dose in 250 ml/m2 twice a day

for 5 days, as a 2 hour iv infusion, at hours 1, 13, 25, 37, 49, 61, 73, 85, 97 and

109 . Total Ara-C dose will be 1000mg /m2/day. Ara-C is started on the first day of

the course.

Children who are <10 kg body weight do not require dose reduction (21) except in

the first month of life, when the dose of Ara-C will be 33mg/kg/day and 16.5 mg/kg

per dose.

2-chlorodeoxyadenosine (2-CdA) 9 mg/m2/day as a 2 hour iv infusion given daily

for 5 days. 2-CdA is started on the second day of the course and is given at hours

23,47,71,95 & 119. The infusion of 2-CdA have should not to be given at the same

time as Ara-C.

For children <10 Kg body weight, the dose of 2-CdA will be 0.3mg/Kg/day (21).

The second course is started in the fifth week after the initiation of therapy

whatever the hematological values.

Dexamethasone eye drops 0.1% or saline eye drops (investigator choice) to both

eyes three times daily for 6 days will be administered with the Ara-C. Eye drops

could be administrated for more than 6 days according to local policy.

G-CSF

Administration of G-CSF 5 micrograms/kg/dose, subcutaneously or intravenously,

given daily until neutrophil recovery occurs, is not contraindicated and is provided

following local policy. Its use, however, should be clearly recorded.

The use of GM-CSF and the use of Peg G-CSF are contraindicated.

Decision rules after 2 courses (figure 2):

The response will be evaluated at week 5-6 after the second cycle (i.e. week 9-10

of 48


from the start of the first cycle unless delayed).

The interval between the first and second cycles is usually 4 weeks, but can be

extended in cases of infectious or metabolic complications. The evaluation after the

second cycle must be done during the fifth week after the start of the 2 nd course.

There are three possibilities:

A) Disease progression in risk organs Stem cell transplantation is

recommended (see protocol of the Histiocyte Society)

B) Improvement of the disease status in risk organs, but active disease still

present: The therapy should be repeated for 1 course of 2 Cda-AraC starting

between 28 and 35 days after the course n°2 followed by 2 courses of 2 CdA at

5mg/m²/day for 5 days, at 3 weekly intervals. For children <10 Kg body weight, the

dose of 2-CdA will be 0.15 mg/Kg/day. At the end of this period, if the status of the

patient is No Active Disease (NAD), maintenance therapy should be started.

However, if at the end of this period, the disease is still active, the treating

physician is required to contact the national study coordinator, for discussion of

further therapy.

C) No disease activity: Start maintenance therapy

Maintenance therapy (figure 3)

Part 1: Two courses of 2- CdA at 5mg/m2/ day for 3 days, given IV as a two hour infusion.

The second course is started at day 21 after the start of the first course provided

the counts have recovered to ANC >750 /mm3 and platelets > 75,000/mm3. For

children <10 Kg body weight, the dose of 2-CdA will be 0.15 mg/Kg/day.

Part 2: Beginning at day 21 from the start of the 2nd course of 2-CdA for a 6 months

duration

Vinblastine 6mg/m² IV every two weeks combined with Corticosteroids

prednisolone 40 mg/m²/day per os, divided into 3 doses per day, for 5 days

of 48


of 48

every two weeks (therefore 12 pulses of vinblastine would be injected given

during a 6 months period)

6 MP Mercaptopurine (6MP) at a dose of 50 mg/m² per os daily

Methotrexate (MTX) at a dose of 20 mg/m² per os once weekly

Part 3: Beginning at day 14 from the start of the last pulse vinblastine for a 12 months

duration:

6 MP at a dose of 50 mg/m² per os daily

Methotrexate MTX at a dose of 20 mg/m² per os once weekly

Oral 6-mercapto purine and oral Methotrexate: How to adapt the therapy in case of side effects If neutrophil count falls below 500/µl treatment will be held until recovery above

these levels and then resumed as tolerated. If neutrophil count falls below 500/µl

on > 2 occasions during continuation, decrease dose of 6-MP or MTX by 25% on

alternation basis upon resumption of therapy. Begin by reducing the 6-MP dose.

Transaminase values of 20N mandate holding therapy until the level returns to

<10N. Persistence of values > 20 N for > 2 weeks requires an evaluation including:

bilirubin, alkaline phosphatase, coagulation tests, albumin, total protein and

hepatitis serologies. A liver biopsy as well a MRI evaluation, a cholangiography

should be considered before additional therapy is given, to help to distinguish

hepatic toxicity from LCH involvement or sclerosing cholangitis. Should therapy be

withheld for myelosuppresion or elevated transaminase, resume therapy at the

correct chronologically.

Course 1 Course 2

Evaluation period

2 CDA: 9m g/m ² IV 2 hours * * * * * * * * * *

Ara-C 500 m g/m ² tw ice a day /IV 2 hours/day ** ** ** ** ** ** ** ** ** **

Days 1 2 3 4 5 6 7 8 9 10 11 12 13 14 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74

Figure 1 : Induction courses: 2 CdA and Ara-C


Figure 2 : Overall shape of the protocol and decision rules after the 2 initial courses

Non active disease Maintenance Therapy Non active disease Maintenance

Therapy

AD better 2 -Cda 9 mg/m² 2 -Cda 5 mg/m² 2 -Cda 5 mg/m² Evaluation AD Intermediate Ara-C 2

2 -Cda 9 mg/m² 2 -Cda 9mg/m² Evaluation course 3 5 days 5 daysAra-C Ara-C 1 Please

course 1 course 2 Duration 28 days Duration 21 days Duration 21 days AD better ContactAD Intermediate Coordinator

Duration 28 days Duration 28 days AD Worse

Worse HSCT

of 48


of 48

Figure 3 : Maintenance therapy

Maintenance therapy

Duration 21 days Duration 21 days Duration 6 months Duration 1 year

2 -Cda 5 mg/m² 2 -Cda 5 mg/m² VLB and 5 days steroid every 2 two weeks: 12 coursesAND 6 MP daily + MTX per os once a week

3 days 3 days 6 MP daily + MTX per os once a week


Supportive care guidelines The clinical condition of patients eligible for this study is usually extremely poor. The

team who is going to administer this protocol should be experienced in the management

of patients receiving very intensive chemotherapy protocols, such as those given in AML

therapy. Therapies such as parenteral nutritional support, antibiotic and antifungal

therapy, prophylactic therapy for aspergillosis and pneumocystis pneumoniae,

immunoglobulin infusion, transfusion support including albumin infusion, are usually a

vital necessity necessary in this subset of patients. By definition, pancytopenia does not

constitute a contraindication to the initial treatment, but any documented infection must

be controlled before starting the therapy.

Antibiotics : Wide spectrum antibiotic and antifungal therapy is recommended to treat

febrile neutropenia according to local policy.

Prophylactic therapy for prevention of fungal disease, particularly aspergillosis infection,

is highly recommended, according to local policy.

Pneumocystis carinii prophylaxis

Oral sulphamethoxazole/trimethoprim 3mg/kg/day of the trimethoprim, divided into 2

doses/day, on 3 consecutive days per week, should be given throughout the study

period and for 12 weeks thereafter

Fluids and parenteral nutrition: the insertion of a double lumen central catheter or

infusion port, prior to therapy start, is encouraged

*During the chemotherapy courses, twice maintenance fluids i.e 3L/m2/24 hours iv (or

200 ml/Kg for children under 10 Kg body weight) should be given except during high

volume chemotherapy infusions.

Urine output should be maintained at least 60% of input, measured 4 hourly.

If the urine output is insufficient, furosemide 0.5 mg/Kg (maximum 20 mg/dose),

should be given

Blood count, renal and liver function studies and electrolytes are to be measured daily

until the results are stable, or more frequently if clinically indicated

Parenteral nutritional support is encouraged

of 48


An albumin infusion is recommended for hypoalbuminemia until the albumin level

remain stable above 30g/L (ie 3.0g/dl)

Intra venous immunoglobulin support is recommended

Blood Products:

All cellular blood products have to be irradiated.

Antiemetic therapy

Could Should be provided following local policy as example:

•Ondansetron (Zofran) 5 mg/m2 po/iv prechemotherapy and 8 hourly p.r.n. (or an

alternative antiemetic)

•Dexamethasone 0.5 mg/Kg/dose (maximum of 8 mg/ dose) given 12 hourly po may be

added for severe nausea and vomiting or a febrile reaction

G-CSF

Administration of G-CSF 5 micrograms/Kg/dose, subcutaneously or intravenously, given

daily until neutrophil recovery occurs, is not contraindicated and may be provided

following local policy. The use of G-CSF must be recorded.

The use of GM-CSF and the use of Peg G-CSF are contraindicated.

of 48


Protocol deviation as a consequence of side effects. The treating physician always has the responsibility to adjust therapy according to the

precise clinical condition of the patient. As this protocol is aimed at a group of patients in

a life threatening situation, with numerous potential complications, decisions to delay

therapy or decrease doses are not recommended, except to manage an acute infection,

or a metabolic complication. Any significant deviation from the protocol (delay more than

2 weeks or administration of less than 80% of recommended dose) has to be reported to

the national study coordinator.

of 48


Pre-treatment evaluation

A complete history, physical examination, including neurologic examination. Height,

weight and body surface area should be recorded.

Documentation of measurable disease, as well as signs and symptoms is required.

Evaluation of all measurable disease by appropriate radiological or ultrasound means

Haematology - complete blood count, platelet count, differential, PT and /or INR, PTT.

(transfusion requirement should be documented)

Chemistry - SGPT, SGOT, bilirubin, total protein, albumin, electrolytes, creatinine,

calcium, phosphate, uric acid, ferritin and ESR.

In case of lung X-ray abnormalities, a CT scan must be performed. Lung function must

be evaluated according to local policy.

HLA typing of the patient is recommended before the first course and family typing

should be done as soon as possible.

Evaluation and response criteria To evaluate the disease activity in Langerhans cell histiocytosis a multi-step approach is

required, starting with a clinical examination and few simple, biological tests and

imaging.

of 48


The following information is supposed to be collected at each evaluation. Variables

Fever

Spleen size

Liver size

Skin area of the skin involvement

Clinical data Pain related to the disease

Nb of RBC transfusion in the week previous evaluation

Nb of Platelets transfusion in the week previous evaluation

Nb of albumin perfusion in the week previous evaluation

Oxygen requirement

Complete Blood Count

ESR

Biochemistry Liver enzyme

Hematology Gamma GT and bilirubin

Albumin

Creatinin

Calcium & atePhosphor

Coagulation testscreen

T cell lymphocyte subsets / phenotype

Ig G A M

Ferritin

imaging Tumoral size in case of soft tissue tumor

Lung CT (only at baseline and at week 9)

Once the information collected; a synthesis of the situation of the patient is done using the

previously published recommendation and the disease for each organ (specially the risk organs)

has to be categorized in Active or Non Active Disease as follows:

of 48


NON ACTIVE DISEASE (NAD)

no evidence of disease

resolution of all signs or symptoms

Regression disease regression of signs or symptoms, no

new lesions ACTIVE DISEASE (AD) stable disease persistence of signs of symptoms, no

new lesions progressive disease progression of signs or symptoms

and/or appearance of new lesions Then the response is considered by comparison of the actual situation with the immediately

previous situation.

There are three categories of response: BETTER

complete resolution NAD

regression

INTERMEDIATE

Mixed new lesions in one site, regression in another site

Stable

unchanged

WORSE

Progression

For this protocol, the timing of the evaluation are as follows:

1. In the week before starting the therapy,

2. At the end of the fourth week (from start of the first course

3. At the end of the fifth week (from start of the second course)

4. 6 months after therapy start

5. 12 months after therapy start

Follow-up and long term outcome

A 5 yr follow up of the patients is recommended in all cases, even if the patient is

withdrawn of from the study for a 5 year period. Once the study period (1 year) is ended,

the follow up has to be organized according to standard recommendation in this disease.

of 48


Drug Information

Cladribine (2-Cda) (Leustatin)

Source and Pharmacology: Cladribine is a synthetic purine nucleoside analogue. It

must be activated by deoxycytidine kinase to its triphosphorylated form. It is then

incorporated into DNA and results in DNA strand breakage and inhibition of DNA

synthesis. The introduction of DNA strand breaks results in a depletion of nicotinamide

adenine dinucleotide and ATP and disruption of cellular metabolism.

Formulation and Stability: Cladribine is supplied in a 10 ml or 20 ml glass vial as a

sterile, isotonic, preservative-free solution containing 10 mg (1 mg/ml) cladribine. The

intact vials should be stored under refrigeration and protected from light. Freezing does

not adversely affect the solution. For further dilution, 5% dextrose containing solutions

are NOT recommended due to cladribine degradation. When diluted in 0.9% NaCl,

solutions should be stored under refrigeration for no more than 8 hours prior to

administration. Seven day infusions may be prepared by diluting the entire 7-day dose in

100ml of bacteriostatic 0.9% NaCl (containing 0.9% benzyl alcohol) and passing the

diluent and drug through a sterile 0.22 micron filter as it is being prepared. When

prepared in this fashion, acceptable chemical and physical stability has been

demonstrated for at least 7 days.

Supplier: Commercially available

Toxicity: The dose limiting toxicity of cladribine is bone marrow suppression, which

may be enhanced by combination with Ara-C. Immunosuppression and increased risk of

opportunistic infections may also be seen. Nausea and vomiting are usually mild.

of 48


Anorexia, diarrhea, headache, fever and chills and rash, pain, swelling and tenderness

at the injection site are fairly common. Rarely, elevation in liver function tests and renal

dysfunction have been reported. Delayed neurotoxicity, characterized by progressive,

irreversible motor weakness of the upper and lower extremities has been reported with

high doses (4-9 times the currently recommended doses). Cumulative thrombocytopenia

requiring prolonged need for platelet transfusions occurs occasionally after multiple

courses. The issue of second malignancy including EBV-induced lymphoproliferative

disease has yet to be clarified. A limitation of fertility is a potential side effect, not already

documented in human.

Dosage and Route of administration: 9 mg/m2/d or 5 mg/m²/d i.v. in 250ml/m2 N/S as

a 2-hours infusion daily for 3-5 days as per the protocol

Cytarabine (Ara-C) (Cytosar-U)

Source and Pharmacology: Cytarabine is a deoxycytidine analogue. It must be tri-

phosphorylated to its active form, ARA-CTP, by deoxycytidine kinase and other

nucleotide kinases. Ara-CTP inhibits DNA polymerase. In addition, ara-CTP is

incorporated into DNA as a false base, causing inhibition of DNA synthesis. It is cell

cycle, S phase specific. Cytarabine does penetrate the blood brain barrier. It is

converted to its inactive form, uracil arabinoside, by pyrimidine nucleoside deaminase.

Approximately 80% of the dose is recovered in the urine, mostly as uracil arabinoside

(ara-U).

Formulation and Stability: Cytarabine is available in multi-dose vials containing 100,

500, 1000 and 2000mg of lyophilized drug. Intact vials can be stored at room

temperature. Reconstitute with sterile water or bacteriostatic water to a recommended

of 48


concentration of 20mg/ml up to a 100mg/ml, except for IT administration. Reconstituted

solution stable for 8 days at room temperature or refrigerated (concentration

dependent).

Supplier: Commercially available

Toxicity: Myelosuppression is the dose limiting adverse effect, with leukopenia and

thrombocytopenia being predominant. Other adverse effects reported commonly include

nausea and vomiting (may be severe at high doses), diarrhea, mucositis, anorexia,

alopecia, skin rash and liver dysfunction. A flu-like syndrome characterized by fever,

muscle and bone aches is common. Less common side effects include allergic reactions

and cellulitis at the injection site. High doses of cytarabine can cause conjunctivitis,

hepatitis, and a group of CNS symptoms including somnolence, peripheral neuropathy,

ataxia and personality changes. CNS symptoms are usually reversible and are more

common in patients who have received previous cranial irradiation. In addition, a

syndrome of sudden respiratory distress progressing to pulmonary edema has occurred.

Dosage and Route of Administration: 500 mg/m2/dose i.v. over 2 hours, every 12

hours for 10 doses.

of 48


Expected toxicity

Drug combination

The most severe life –threatening toxicity resulting from a combination of the 2 drugs is

likely to be fever associated with neutropenia and sepsis

Cladribine(2-CDA) (Leustatin)

* Transient myelosuppression commonly requiring blood product support. Infections are

common and appear to be associated with the degree of neutropenia.

* Cumulative myelotoxicity especially prolonged thrombocytopenia can occur after

multiple cycles. Thrombocytopenia lasting up to 6 months has been observed

* Fever is common but does not appear to be a direct side effect of the drug and

appears to correspond to periods of maximal cell lysis in patients with LCH or periods of

neutropenia

* Immunosuppression with monocytopenia and T-cell depletion occurs which may last

for years. Significant opportunistic infections are uncommon except in the leukemic

population.

* 2-CdA does not appear to increase the incidence of second malignancies. However

prolonged EBV infection and EBV–induced lympho proliferative disease have been

rarely reported after high cumulative doses.

* Severe irreversible neurotoxicity and nephrotoxicity has been observed and appears to

be dose-related, occurring at doses of 0.4-0.5 mg/kg (16-20 mg/m²) day for 7-14 days in

combination with Cyclophosphamide and Total Body Irradiation.

of 48


* The neurotoxicity seen in adults with AML when the dose reached 19-21mg/m2 was an

axonal peripheral polyneuropathy affecting lower limbs more than upper, and proximal

muscles more than distal. At the doses suggested in this protocol, these toxicities

appear to be rare, although neurotoxicity at lower doses in patients with pre-existing

neurologic conditions have been described.

*Mild nausea,abdominal pain, diarrhoea, fatigue, headache, skin rash and elevations of

liver enzymes may occur.

•Pulmonary toxicity and cardiotoxicity are not usually seen at these doses.

•Sterility has been observed in animal models but is not documented in human.

No significant drug interactions have been reported to date.

Cytarabine (Ara-C) (Cytosar-U)

* myelosuppression, nausea and vomiting, gastrointestinal mucosal damage including

stomatitis, alopecia

* a syndrome of fever, skin rash, conjunctivitis, malaise, myalgia and chest pain has

been reported in children on standard doses. Steroid eye-drops are recommended when

high dose Ara-C is given

* neurotoxicity--mainly cerebellar dysfunction, primarily associated with high dose

Ara-C, other complications predisposing conditions include renal and liver toxicty.

Ara-C should be discontinued immediately if nystagmus or ataxia occur.

of 48


Toxicity reporting

Toxicity should be reported using standard WHO criteria / Appendix 2; using a specific

sheet / Appendix 6.

Any unexpected toxicity (WHO grade 4) must be reported to national study

coordinator within 48 hours, as must any death, whatever the cause of death.

Fever, prolonged and severe pancytopenia are considered as EXPECTED events during

the two initial courses of 2-Cda and Ara-C and as UNEXPECTED during the

maintenance therapy.

The referring physician of the patient is responsible for the reporting of all unexpected

severe toxicities to the study coordinator who is the national coordinator in EU, or the

coordinator of the study in each center in north America.

The study coordinator must inform the chairman of the study within 48 hours and the

chairman must inform data monitoring safety committee of any unexpected event within

48 hours.

The data safety monitoring committee in turn must provide advice regarding the

interpretation of the unexpected event within a week and must make a recommendation

about the continuation of the study, according to the arrest rules. The study coordinator

will then inform the study committee.

Once the advice of the committee has been received, a final decision is taken, which will

then be transmitted to each national authority that has approved this clinical trial.

of 48


Statistical considerations

Langerhans cell histiocytosis is a rare disease. From published surveys of LCH patients,

it is apparent that the inclusion criteria used here restrict this study to a very limited

subset of the patients, likely representing less than 5% of all newly diagnosed LCH.

There will likely be no more than 12 patients a year eligible for study, if all the

participating countries include all their eligible patients.

Two important considerations have been taken into account when restricting the

inclusion criteria.

First, this group of patients has an extremely poor outcome with standard approaches,

compared to other LCH patients, who have an excellent short-term outcome. Secondly,

the expected toxicities of the drug combination being evaluated in this study are

significantly greater than the complications seen with standard first line therapy in LCH.

So the restrictive inclusion criteria are used here to protect better prognosis LCH

patients from an unduly toxic approach.

The limited expected enrollment does not allow for a randomized trial. A phase II, open

labeled trial design has therefore been chosen.

The short term response rate, as for most phase II studies, will be used as the major

end point of the study, based on the standard criteria for response in risk organs used in

the previous LCH clinical trials (Non Active Disease/ Active Disease better or stable or

worse). With regards to literature (1, 3, 5, 7), the best response rate of historical controls

in this group of patient is about 25%. So, a response rate of less than 25% is

unacceptable and that a response rate of 50% is achievable with this protocol.

A Simon two-stage phase II study is designed with an unacceptable response rate of

25% and a promising response rate of 50%.

13 patients will be included in the first stage. If 3 responses are observed, the study

will be stopped and the treatment declared ineffective. If 4 responses are observed, 17

additional patients will be included.

At the end of the study (after the inclusion of 30 patients), the treatment will be declared

promising if 11 responses are observed and ineffective if 10 responses are

observed.

of 48


The error rate (accepting a poor treatment) will be 0.09 and the error rate (rejecting

a promising treatment) will be 0.08.

Summary of the trial

Type: Phase II open labeled study

Major end point: Response rate at week 9-10 after therapy initiation. Good response is

defined by Non Active disease or Active disease Better. Poor response is defined by

Active disease Worse or Intermediate or Early death, whatever the cause of death

Plan: Simon Plan/ Two steps

Number of patients: Total 30 (13 at step 1 and 17 at step 2)

Step 1: No. of patients 13:

Arrest Rule: Step 1 (Interim analysis): If there are less than 4 responses, the treatment

is considered as non effective. The trial is stopped

Step 2: No. of patients: 17

Step 2: If there are less than 11 responses amongst the total number of patients (n=30)

the treatment is considered as non effective. Otherwise, the treatment is considered as

effective.

The error rate (accepting a poor strategy) will be 9% and the error rate (rejecting a

promising strategy) will be 8%.

of 48


Appendix

of 48


Appendix 1 : Risk organs definition

Hematopoetic involvement:

Anemia haemoglobin <10 g/dl, infants < 9 g/dl Leukocytopenia leukocytes < 4,0 x109/l, <4000/mm3

Thrombocytopenia platelets < 100 x 109/l <100,000/mm3

with or without bone marrow involvement. Bone marrow involvement is defined as the demonstration of CD1a positive cells on bone marrow smears. The clinical significance of CD1a positivity in the bone marrow remains to be proven.

Spleen involvement:

enlargement > 2 cm below costal margin (proven by sonography)

Liver involvement:

enlargement >3 cm below costal margin (proven by sonography) and/or total protein < 5,5 g/dl, albumin < 2,5 g/dl (not due to protein losing enteropathy) ascites edema hyperbilirubinemia with total bilirubin > 1,5 g/dl

Lung involvement:

typical changes on high resolution computed tomography (HR-CT) and/or histopathological diagnosis

of 48


of 48

Appendix 2 : WHO toxicity criteria

PARAMETER

GRADE 1

GRADE 2

GRADE 3

GRADE 4

HEMATOLOGY

Hemoglobin > 3 mo.- < 2 y.o.

9.0-9.9

7.0-8.9

<7.0

Cardiac Failure 2ndary to anemia

Hemoglobin > = 2 y.o.

10-10.9

7.0-9.9

<7.0

Cardiac Failure 2ndary to anemia

Abs Neutrophil Ct

750-1200

400-749

250-399

<250

Platelets

50,000-75,000

25,000-49,999

<25,000 or bleeding

PT

1.1-1.25xN

1.26-1.5xN

1.51-3.0xN

>3xN

PTT

1.1-1.66xN

1.67-2.33xN

2.34-3.0xN

>3xN

GASTROINTESTINAL

Bilirubin

1.1-1.9xN

2.0-2.9xN

3.0-7.5xN

>7.5xN

AST (SGOT)

1.1-4.9xN

5.0-9.9xN

10.0-15.0xN

>15.0xN

ALT (SGPT)

1.1-4.9xN

5.0-9.9xN

10.0-15.0xN

>15.0xN

GGT

1.1-4.9xN

5.0-9.9xN

10.0-15.0xN

>15.0xN

Pancreatic Amylase

1.1-1.4xN

1.5-1.9xN

2.0-3.0xN

>3.0xN

Total Amylase + Lipase*

1.1-1.4xN

1.5-2.4xN

2.5-5.0xN

>5.0xN

Uric Acid

7.5-9.9

10-12.4

12.5-15.0

>15.0 or Gout

CPK

See Neuromuscular Toxicity

Abdominal Pain

Mild

Moderate- No Rx Needed

Moderate- Rx Needed

Severe- Hospital and Rx

Diarrhea

Soft stools

Liquid stools

Liquid Stools and Mild Dehydration Bloody stools

Dehydration requiring IV therapy or Hypotensive Shock

Constipation

Mild

Moderate

Severe

Distention and Vomiting

Nausea

Mild

Moderate- Decreased po intake

Severe- Little po intake

Unable to ingest food or fluid for >24 hours

Vomiting

<1 episode/day

1-3 episodes/day or duration >3d

>3 episodes/day or duration >7d

Intractable Vomiting

PARAMETER

GRADE 1

GRADE 2

GRADE 3

GRADE 4

RENAL AND ELECTROLYTES

CREATININE

2 Month-2 Years

0.6-0.8

0.9-1.1

1.2-1.5

>1.5

2 Years-Adolescent

0.7-1.0

1.1-1.6

1.7-2.0

>2.0

Adolescents

1.0-1.7

1.8-2.4

2.5-3.5

>3.5

Creatinine Clearance

60-75

cc/min/1.73 m2

50-59

cc/min/1.73 m2

35-49

cc/min/1.73 m2

<35

cc/min/1.73 m2

ELECTROLYTES

High Sodium

145-149

150-155

>155 or mental status changes

Low Sodium

130-135

129-124

<124 or mental status changes

High Potassium

5.0-5.9

6.0-6.4

6.5-7.0

>7.0 or Cardiac arrhythmias

Low Potassium

3.0-3.5

2.5-2.9

2.0-2.4

<2.0

High Calcium

10.5-11.2

11.3-11.9

12.0-12.9

>=13.0

Low Calcium

7.8-8.4

7.0-7.7

6.0-6.9

<6.0

Low Magnesium

1.2-1.4

0.9-1.1

0.6-0.8

<0.6 or Cardiac arrhythmias

Hypoglycemia

55-65

40-54

30-39

<30 or Mental status changes

Hyperglycemia

116-159

160-249

250-400

>400 or Ketoacidosis

Proteinuria

Tr-1+ <150 mg/day

2+ 150-499 mg/day

3+ 500-1000 mg/day

4+, or nephrotic syndrome >1000 mg/day

Hematuria

Microscopic <25 cells/hpf

Microscopic >=25 cells/hpf

Gross

Obstruction or Transfusion requirement

Comments Calcium values are corrected for albumin concentration. CrCl values do not apply to infants <2 months old.


OTHER

SYMPTOM

GRADE 1

GRADE 2

GRADE 3

GRADE 4

Allergy

Pruritis without Rash

Pruritic Rash

Mild Urticaria

Severe Urticaria Anaphylaxis, Angioedema

Drug Fever (Rectal)

38.5-40

>40

Sustained Fever: >40, >5 days

Cutaneous

Diffuse maculo- papular rash, dry desquamation

Vesiculation, ulcers

Exfoliative dermatitis, Stevens-Johnson or Erythema multiforme, Moist desquamation

Stomatitis

Mild discomfort

Painful, difficulty swallowing, but able to eat and drink

Painful: unable to swallow solids

Painful: requires IV fluids

of 48


CENTRAL NERVOUS SYSTEM

SYMPTOM

GRADE 1

GRADE 2

GRADE 3

GRADE 4

Seizures

None

1 Uncomplicated Sz +/- Temp Elevation

1 Sz/Month for >=2 Consecutive Months Or 3 Sz over 6 Months; No Temp Elevation

>1 Sz/Month; No Temp Elevation; No Decrease in Sz Frequency Despite dose reduction

Headache

<=1/Month <2 Hrs duration Mild

>1/Month >2 Hrs Duration Moderate to Severe Responds to non-narcotic analgesia or prophylaxis

>2/Month >2 Hrs Duration Moderate to Severe Responds to narcotic analgesia, or does not respond to prophylaxis

>4/Month; >2 Hrs Duration; Moderate to Severe; Non-Responsive to narcotic Analgesia; or persistently Recurrent despite prophylaxisNo decrease in frequency or Severity despite dose reduction

Mental Status And Behavior

Changes which do not Affect Function

Changes requiring pharmacologic or other therapy; or mild lethargy, sedation or somnolence which resolves with rest

Changes not improved by drugs or other therapies; or onset of confusion, memory impairment, lethargy, sedation, or somnolence which does not respond to rest

Onset of delirium, obtundation, coma, or psychosis, or Grade 3 toxicity which does not respond to dose reduction

Behavior refers to the development of attention deficits with or without hyperactivity, depression, mania, agitation, sleep disorders, phobias, obsessive-compulsive behaviors, or anxiety. Mental status refers to the level of consciousness, memory function, language and analytical operations, and non-dominant hemisphere functioning. Alternative explanations should be sought.

Balance & Posture

None

None

Ataxia, dizziness, vertigo, tremor, impaired postural balance

Onset of movement disorder; or Grade 3 toxicity which does not respond to dosage adjustment

"Ataxia" can be mistakenly diagnosed in the face of central weakness or peripheral neuropathy, which should not be considered a drug toxicity of this category. Movement disorders refer to tardive or other dyskinesias, dystonias, chorea, or ballismus. Alternative explanations should be sought.

of 48


SYMPTOM

GRADE 1

GRADE 2

GRADE 3

GRADE 4

Visual

None

Blurriness, diplopia, or horizontal nystagmus of < 1 hour duration, with spontaneous resolution

> = 1 episode of Grade 2 symptoms per week, or an episode of Grade 2 Sx lasting 1 hour with spontaneous resolution by 4 hours or vertical nystagmus

Decrease in visual acuity, visual field deficit, or oculogyric crisis, or Grade 3 Sx which persist after dose reduction

Myelopathy

None

None

None

Myelopathic/spinal cord symptoms, such as: Pyramidal tract weakness and disinhibition, sensory level, loss of proprioception, bladder/bowel dysfunction

PERIPHERAL NERVOUS SYSTEM

Neuropathy/ Lower Motor Neuronopathy

None

Mild transient Paresthesia only

Persistent or progressive paresthesias, burning sensation in feet, or mild dysesthesia; no weakness; mild to moderate deep tendon reflex changes; no sensory loss

Onset of significant weakness, decrease or loss of DTRs, sensory loss in "stocking glove" distribution, radicular sensory loss, multiple cranial nerve involvement; bladder or bowel dysfunction, fasciculations, respiratory embarrassment from chest wall weakness. Grade 3 symptoms which do not resolve with dose reduction

Infectious agents other than HIV can precipitate a neuropathy and should be considered, especially CMV. Neuropathies which do not resolve after dose reduction or discontinuation should be pursued for alternative infectious or non-infectious etiologies, since drug-related neuropathies will usually resolve after dose reduction or drug discontinuation. It should be borne in mind that many subjects will worsen for up to one month after drug discontinuation prior to improvement ("coasting"). Abnormalities should be confirmed by nerve conduction studies (NCS) +/-electromyographic studies (EMG). Myopathy or Neuromuscular Junction Impairment

Normal or mild (<2 x N) CPK elevation

Mild proximal weakness and/or atrophy not affecting gross motor function. Mild myalgias, +/- mild CPK elevation (<2 x N)

Proximal muscle weakness and/or atrophy affecting motor function +/- CPK elevation; or severe myalgias with CPK >2 x N; Consider confirmatory EMG and/or muscle bx

Onset of myasthenia-like symptoms (fatiguable weakness with external, variable ophthalmoplegia and/or ptosis), or neuromuscular junction blockade (acute paralysis) symptoms (confirm with EMG); or Grade 3 symptoms which do not resolve on dose adjustment; confirm with muscle bx

HIV can produce a myopathy, and should be differentiated. Drug-induced myopathy can be accompanied by normal CPK levels. On occasion, neuropathic or central weakness can mimic myopathic weakness.

of 48


of 48

SYMPTOM

GRADE 1

GRADE 2

GRADE 3

GRADE 4

Clinical symptoms not otherwise specified in this table

No therapy; monitor condition

May require minimal intervention and monitoring

Requires medical care and possible hospitalization

Requires active medical intervention, hospitalization, or hospice care

Laboratory values not otherwise specified in this table

Abnormal, but requiring no immediate intervention; follow

Sufficiently abnormal to require evaluation as to causality and perhaps mild therapeutic intervention, but not of sufficient severity to warrant immediate changes in study drug

Sufficiently severe to require evaluation and treatment, including at least temporary suspension of study drug

Life-threatening severity. Requires immediate evaluation, treatment, and usually hospitalization. Study drug must be stopped immediately and should not be restarted until the abnormality is clearly felt to be caused by some other mechanism that study drug.

Appendix 3: Data monitoring Time table

Each evaluation must be communicated to the coordinator of the study in a timely

fashion.

The following variables will be used to define the inclusion criteria and will be used

in the evaluation of the disease status during the follow up of the patients:

Variables Week -1 End Course 1

End Course 2

Week 26 Week 52

Fever + Spleen size + + + + + Liver size + + + + + Skin area + + + + + Clinical data Pain related to the

disease + + + + +

Nb of RBC transfusion

+ + + + +

Nb of Platelets transfusion

+ + + + +

Nb of albumin perfusion

+ + + + +

Oxygen requirement + + + + + ESR + + + + + Complete Blood

Count + + + + +

Biochemistry Liver enzyme + + + + + Hematology Gamma GT or

bilirubin + + + + +

Albumin + + + + + Creatinin + + + + + Calcium Phosphor + + + + + Coagulation test + + + + + T cell lymphocyte

phenotype + + + + +

Ig G A M + + + + + Ferritin + + + + + imaging Tumoral size in case

of soft tissue tumor + + + + +

Lung CT (only at baseline and at week 9)

+ +


Appendix 4: Informed consent

Informed consent : Must be written in the language of the patient / guardians

of 48


Appendix 5 : LCH 2005 S Inclusion sheet (2 pages) To be faxed or mailed to

Dr J Donadieu Service d’hémato oncologie Pédiatrique

Hopital Trousseau 26 avenue du Dr Netter

75012 Paris FRANCE

FAX : 33 1 44 73 65 73

by mail : [email protected]

Patient initial :

Inclusion date:

Informed consent : Date of signature:

Referring physician : name and address including e mail:

Reference pathologist: name:

Signature of the referring physician:

of 48


LCH 2005 S Inclusion sheet (page 2) Patient Initial !___!___!___! Referring physician: Name: All the 5 following criteria must be present: a biopsy-proven definitive diagnosis of LCH

AND

Risk organ involvement (Appendix 1)

AND

Failure of initial therapy defined by disease progression in one or more risk organs except

solely lung, after at least 6 weekly doses of vinblastine and 28 days of corticosteroid at a minimum

dose of 40 mg/m², with or without the addition of a third drug. The patient will be eligible even if

he/she has not been registered or treated “according to” the LCH-III protocol, however a similar

initial treatment approach is required before inclusion on LCH-S-2005. If drugs other than

vinblastine and corticosteroid have been given in the two months prior to the inclusion in this study,

the coordinator of the study has to validate the inclusion in writing. Patients with reactivation in risk

organ(s) except solely lung, resistant in one or more risk organs after at least 6 weekly doses of

vinblastine and 28 days of corticosteroid at a minimum dose of 40 mg/m², may be enrolled in the

study.

AND

Informed consent. All patients or their legal guardians (if the patient is below the legal age of

consent), must sign a research ethics board approved consent form indicating their awareness of

the investigational nature and the risks of this study. When appropriate, younger patients will be

included in all discussions in order to obtain verbal assent.

Exclusion criteria: The presence of any of the following criteria will exclude the patient from study: Isolated sclerosing cholangitis, with an inadequate liver function, as defined by biological liver

abnormalities and typical imaging without evidence of active LCH as the only evidence of risk organ

involvement

Isolated lung involvement at any age as well as systemic disease with lung disease as the only risk organ involvement Inadequate renal function as defined by serum creatinine > 3x normal for age.

Pregnancy or breast-feeding.

of 48


Appendix 6 : LCH 2005 S Toxicity report sheet in case of severe adverse event OR DEATH Patient Initial !___!___!___! Name of the physician:

Contact with referent physician: Description of event ......................................................................

Date of onset (DD / MM/YY) I__I__I I__I__I I__I__I

Date of end (DD / MM/YY) I__I__I I__I__I I__I__I

Did the event modify a pre-existing condition

No Yes Progression Stable Regression Not applicable

Did the event result in death No Yes

If death: Main cause

If death: LCH status at the time of death

No LCH activity LCH activity involving risk organs LCH activity but only in NON risk organs

WHO grade 1 2 3 4

Frequency of the event

Unique Temporary Permanent Not assessable

Relation with the therapy NO DOUBTFUL PROBABLE NOT ASSESSABLE

Symptomatic therapy: No

Yes .........................................

Hospitalization or prolongation If yes duration

No Yes Total number of days......................................

Withdrawal of the therapy No Yes Temporary

Other potential causes of adverse event ? If yes detailed :

No Yes …………………..................

Outcome Recovered Ongoing Other : ..................................................................

Comments

of 48


References 1. Gadner H, Grois N, Arico M, Broadbent V, Ceci A, Jakobson A et al. A randomized trial of treatment for

multisystem langerhans'cell histiocytosis. Journal of Pediatrics 2001;138:728-34.

2. Berry DH, Gresik MV, Humphrey GB, Starling K, Vietti T, Boyett J et al. Natural history of histiocytosis X: a Pediatric Oncology Group Study. Med.Pediatr.Oncol. 1986;14:1-5.

3. Gadner H, Heitger A, Ritter J, Göbel U, Janka GE, Kühl J et al. Langerhanszell- Histiozytose im Kindesalter - Ergebnisse der DAL-HX 83 Studie. Klinishe Pädiat 1987;199:173-82.

4. Kilpatrick SE, Wenger DE, Gilchrist GS, Shives TC, Wollan PC, Unni KK. Langerhans' cell histiocytosis (Histiocytosis X) of bone; A clinicopathologic analysis of 263 pediatric and adult cases. Cancer 1995;76:2471-84.

5. The French Langerhans' Cell Histiocytosis Study Group. A multicentre retrospective survey of Langerhans' cell histiocytosis : 348 cases observed between 1983 and 1993. Arch Dis Child 1996;75:17-24.

6. Willis B, Ablin A, Weinberg V, Zoger S, Wara WM, Matthay KK. Disease course and late sequelae of Langerhans cell histiocytosis: 25-year experience at the University of California, San Francisco. J Clin Oncol 1996;14:2073-82.

7. Minkov M, Grois N, Heitger A, Potschger U, Westermeier T, Gadner H. Response to initial treatment of multisystem Langerhans cell histiocytosis: an important prognostic indicator. Med.Pediatr Oncol. 2002;39:581-5.

8. Braier J, Latella A, Balancini B, Castanos C, Rosso D, Chantada G et al. Outcome in children with pulmonary Langerhans cell Histiocytosis. Pediatr.Blood Cancer 2004;43:765-9.

9. Dimopoulos MA, Theodorakis M, Kostis E, Papadimitris C, Moulopoulos LA, Anastasiou-Nana M. Treatment of Langerhans cell histiocytosis with 2 chlorodeoxyadenosine. Leuk.Lymphoma 1997;25:187-9.

10. Frost JD, Wiersma SR. Progressive Langerhans cell histiocytosis in an infant with Klinefelter syndrome successfully treated with allogeneic bone marrow transplantation. J.Pediatr.Hematol.Oncol. 1996;18:396-400.

11. Grau J, Ribera JM, Tormo M, Indiano JM, Vercher J, Sandoval V et al. [Results of treatment with 2-chlorodeoxyadenosine in refractory or relapsed Langerhans cell histiocytosis. Study of 9 patients]. Med.Clin.(Barc.) 2001;116:339-42.

12. Saven A, Figueroa ML, Piro LD, Rosenblatt JD. 2-Chlorodeoxyadenosine to treat refractory histiocytosis X. N.Engl.J.Med. 1993;329:734-5.

13. Saven A, Foon KA, Piro LD. 2-Chlorodeoxyadenosine-induced complete remissions in Langerhans-cell histiocytosis. Ann.Intern.Med. 1994;121:430-2.

14. Saven A, Piro LD. 2-Chlorodeoxyadenosine: a potent antimetabolite with major activity in the treatment of indolent lymphoproliferative disorders. Hematol Cell Ther 1996;38 Suppl 2:93-101.

15. Saven A, Burian C. Cladribine activity in adult langerhans-cell histiocytosis. Blood 1999;93:4125-30.

16. Stine KC, Saylors RL, Williams LL, Becton DL. 2-Chlorodeoxyadenosine (2-CDA) for the treatment of

of 48


of 48

refractory or recurrent Langerhans cell histiocytosis (LCH) in pediatric patients. Med.Pediatr.Oncol. 1997;29:288-92.

17. Stine KC, Saylors RL, Saccente S, McClain KL, Becton DL. Efficacy of continuous infusion 2-CDA (cladribine) in pediatric patients with Langerhans cell histiocytosis. Pediatr.Blood Cancer 2004;43:81-4.

18. Weitzman S, Wayne AS, Arceci R, Lipton JM, Whitlock JA. Nucleoside analogues in the therapy of Langerhans cell histiocytosis: a survey of members of the histiocyte society and review of the literature. Med.Pediatr.Oncol. 1999;33:476-81.

19. Akkari V, Donadieu J, Piguet C, Bordigoni P, Michel G, Blanche S et al. Hematopoietic stem cell transplantation in patients with severe Langerhans cell histiocytosis and hematological dysfunction: Experience of the French Langerhans Cell Study Group. Bone Marrow Transplant. 2003;31:1097-103.

20. Steiner M, Matthes-Martin S, Peters C, Grois N, Minkov M, Attarbaschi A et al. Stem cell transplantation following reduced intensity conditionning regimen as therapeutic option for severe refractory langerhans cell histiocytosis. Histiocyte society XX meeting 2004;Abstract.

21. Bernard F, Thomas C, Bertrand Y, Munzer M, Landman-Parker J, Ouache M et al. Report of multicenter pilot study of 2-CdA and Ara-C combined chemotherapy in refractory Langerhans cell histiocytosis with hematological dysfunction. Eur J Cancer 2005;In press.

22. Egeler RM, de Kraker J, Voute PA. Cytosine-arabinoside, vincristine, and prednisolone in the treatment of children with disseminated Langerhans cell histiocytosis with organ dysfunction: experience at a single institution. Med.Pediatr.Oncol. 1993;21:265-70.

23. Crews KR, Gandhi V, Srivastava DK, Razzouk BI, Tong X, Behm FG et al. Interim comparison of a continuous infusion versus a short daily infusion of cytarabine given in combination with cladribine for pediatric acute myeloid leukemia. J.Clin.Oncol. 2002;20:4217-24.

24. Kornblau SM, Gandhi V, Andreef HM, Beran M, Kantarjian HM, Koller CA et al. Clinical and laboratory studies of 2-chlorodeoxyadenosine cytosine arabinoside for relapsed or refractory acute myelogenous leukemia in adults. Leukemia 1996;10:1563-9.

25. Donadieu J, Piguet C, Bernard F, Barkaoui M, Ouache M, Bertrand Y et al. A new clinical score for disease activity in Langerhans cell histiocytosis. Pediatr Blood Cancer 2004;43:1-7.

26. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin.Trials 1989;10:1-10.

the langerhans cell histiocytosis salvage therapy … · langerhans cell histiocytosis (lch) ......

Documents