Download A Phase II study for LCH resistant patient with 2 CDA

LCH-S-2005
An International Phase II Study
evaluating the combination of
Cladribine (2 CdA) + Cytarabine Cytosinearabinoside 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
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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
e-mail: [email protected]
Jorge Braier
Pediatric Hemato / Oncology
Hospital Garrahan
Combate de los Pozos, 1881
Buenos Aires 1245 Argentina
P: 54 1 43084300
F 54 11 43085325
e-mail: [email protected]
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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
e-mail: [email protected]
Nicole Grois
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]
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
e-mail: [email protected]
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
e-mail: [email protected]
Sheila Weitzman
The Hospital for Sick Children
555 University avenue
Toronto, Ontario, Canada
Tel 416 813 5872
Fax: 416 813 5327
e-mail: [email protected]
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
e-mail: [email protected]
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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
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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
definition
failure
(3;7)
DAL
HX83
Vinblastine
VP16
and
corticosteroid
Vinblastine
VP16
and
corticosteroid
Vinblastine
or
VP16
and
corticosteroid
Mainly
vinblastine and
corticosteroid
AD Worse
(7)
DAL
90
HX
(1)
LCH I
(5)
French
survey
for
of
Number
of
resistant
patients
Survival
rate %
9
11%
AD Worse
25
40%
Progression
of the disease
13
0%
AD Worse
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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
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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
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count, albumin level, liver function tests), as well as imaging studies. Further
validation of this scoring system however, will require a prospective, multiinstitutional evaluation and for this present study the established LCH III evaluation
system will be utilized.
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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.
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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:
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 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.
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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.
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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
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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
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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.
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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
Figure 1 : Induction courses: 2 CdA and Ara-C
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
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Figure 2 : Overall shape of the protocol and decision rules after the 2 initial courses
Non active disease
AD better
AD Intermediate
2 -Cda 9 mg/m²
Ara-C
course 1
2 -Cda 9mg/m²
Ara-C
course 2
Duration 28 days
Duration 28 days
Evaluation
1
Maintenance
Therapy
2 -Cda 9 mg/m²
Ara-C
course 3
Duration 28 days
W orse
Non active disease
2 -Cda 5 mg/m²
2 -Cda 5 mg/m²
5 days
5 days
Duration 21 days
HSCT
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Duration 21 days
Maintenance
Therapy
Evaluation
2
AD better
AD Intermediate
AD W orse
Please
Contact
Coordinator
Salvage therapy S 2005
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Figure 3 : Maintenance therapy
Maintenance therapy
Duration 21 days
Duration 21 days
2 -Cda 5 mg/m²
2 -Cda 5 mg/m²
3 days
3 days
Duration 6 months
Duration 1 year
VLB and 5 days steroid every 2 two weeks: 12 courses
AND
6 MP daily + MTX per os once a week
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6 MP daily + MTX per os once a week
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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
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 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.
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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.
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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.
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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:
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NON ACTIVE DISEASE (NAD)
no evidence of disease
resolution of all signs or symptoms
Regression disease
regression of signs or symptoms, no
new lesions
persistence of signs of symptoms, no
new lesions
progression of signs or symptoms
and/or appearance of new lesions
stable disease
ACTIVE DISEASE (AD)
progressive disease
Then the response is considered by comparison of the actual situation with the immediately
previous situation.
There are three categories of response:
complete resolution
NAD
BETTER
regression
Mixed
new lesions in one site, regression
in another site
Stable
unchanged
INTERMEDIATE
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.
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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.
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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 triphosphorylated 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
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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.
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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.
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* 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.
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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.
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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.
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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%.
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Appendix
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Appendix 1 : Risk organs definition

Hematopoetic involvement:
Anemia
Leukocytopenia
Thrombocytopenia
haemoglobin <10 g/dl, infants < 9 g/dl
leukocytes < 4,0 x109/l, <4000/mm3
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
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Appendix 2 : WHO toxicity criteria
PARAMETER
GRADE 1
GRADE 2
GRADE 3
GRADE 4
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
50,000-75,000
25,000-49,999
<25,000 or bleeding
HEMATOLOGY
Platelets
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
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
ModerateNo Rx Needed
ModerateRx Needed
SevereHospital 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
ModerateDecreased po intake
SevereLittle po intake
Unable to ingest food or fluid for
>24 hours
Vomiting
<1
episode/day
1-3 episodes/day
duration >3d
GASTROINTESTINAL
or
>3
episodes/day
duration >7d
Page 36 of 48
or
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
50-59
2
cc/min/1.73 m
35-49
2
cc/min/1.73 m
<35
2
2
cc/min/1.73 m
cc/min/1.73 m
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.
Salvage therapy S 2005
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OTHER
SYMPTOM
GRADE 1
GRADE 2
GRADE 3
GRADE 4
Allergy
Pruritis without
Rash
Pruritic Rash
Mild Urticaria
Severe Urticaria
Anaphylaxis, Angioedema
38.5-40
>40
Sustained Fever:
>40, >5 days
Diffuse maculopapular rash, dry desquamation
Vesiculation,
ulcers
Exfoliative dermatitis,
Stevens-Johnson
or
Erythema
multiforme, Moist desquamation
Painful, difficulty swallowing, but
able to eat and drink
Painful: unable
to
swallow
solids
Painful: requires IV fluids
Drug
(Rectal)
Fever
Cutaneous
Stomatitis
Mild
discomfort
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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 prophylaxis
No 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.
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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
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
PERIPHERAL NERVOUS SYSTEM
Neuropathy/
Lower
Motor
Neuronopathy
None
Mild transient
Paresthesia only
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 drugrelated 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.
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SYMPTOM
GRADE 1
GRADE 2
GRADE 3
GRADE 4
Clinical
symptoms not
otherwise
specified in this
table
No
therapy;
monitor
condition
May
require
intervention
monitoring
minimal
and
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.
Page 41 of 48
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:
Clinical data
Biochemistry
Hematology
imaging
Variables
Week -1
End
Course 1
End
Course 2
Week 26
Week 52
Fever
Spleen size
Liver size
Skin area
Pain related to the
disease
Nb
of
RBC
transfusion
Nb
of
Platelets
transfusion
Nb
of
albumin
perfusion
Oxygen requirement
ESR
Complete
Blood
Count
Liver enzyme
Gamma
GT
or
bilirubin
Albumin
Creatinin
Calcium Phosphor
Coagulation test
T cell lymphocyte
phenotype
Ig G A M
Ferritin
Tumoral size in case
of soft tissue tumor
Lung CT (only at
baseline
and
at
week 9)
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Salvage therapy S 2005
December 2005
Appendix 4: Informed consent
Informed consent : Must be written in the language of the patient / guardians
Page 43 of 48
Salvage therapy S 2005
December 2005
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:
Page 44 of 48
Salvage therapy S 2005
December 2005
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.
Page 45 of 48
Salvage therapy S 2005
December 2005
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 preexisting condition
Did the event result in death
No
Yes
Progression
Stable
Regression
Not applicable
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
Withdrawal of the therapy
No
Yes
Temporary
Other potential causes of adverse
event ?
If yes detailed :
Outcome
No
Yes
Total number of days......................................
…………………..................
Recovered
Ongoing
Other : ..................................................................
Comments
Page 46 of 48
Salvage therapy S 2005
December 2005
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