All Ic Append

APPENDIX 1
LOGISTICS & KEY DATA ON: PATIENT, DIAGNOSIS, THERAPY, OUTCOME & TOXICITY
1.0 1.1 1.2 1.3 1.3.a 1.3.b 1.3.c 1.3.d 1.3.e 1.3 1.4 Logistics Baseline-Data & Initial-Response Form Follow-up Form Variables in ALL IC-BFM 2002 Database Baseline Data Therapy Therapy Realization & Toxicity FU SCT Add. Code List Cytogenetics
SAE Form
Diagnostics in ALL IC-BFM 2002

Appendix 1.0
Mandatory
At diagnosis
Day 8
Day 15
Day 33
Day 52
Day before Prot. Month 24 mM/M/1.HR' block

+
Reference center: Morphology (PB/BM/LP) Therapy Response & Remission Status

6 PB 6 BM* 6 BM 6 BM
++
6 PB smears 6 BM smears 2 cytospin smears 6 PB 6 BM 6 BM
6 BM*
Immunophenotyping (DNA index, MRD)

_ _ 2 ml BM _ 2 ml BM
1 PB + 1 BM smear 2 ml EDTA BM 5 ml EDTA PB 2 ml PB+BM* 2 ml BM 2 ml BM _ 2 ml BM
Molecular Genetics +MRD Diagnostics

_ _
1 PB + 1 BM smear 2 ml EDTA BM 5 ml EDTA PB
Cytogenetics
1 PB + 1 BM smear 3 ml heparin. BM 3 ml heparin. PB
10 ml EDTA BM if WBC < 2,000/L in PB _ _ _
* Optional NR D+33
++
NR D+52
ALL IC-BFM 2002
Appendix 1.1
ALL IC BFM 2002

Baseline-Data & Initial-Response Form
National Study Coordinator: Address: Tel.: Fax: Initials (Family name/First name) / UPN Center Sex (M/F) Date of Birth dd/mm/yyyy)
HISTORY:
Pre-existing disease: no yes no yes
Previous treatment with corticosteroids or cytostatic agents: Previous treatment timing:
within 4 weeks before diagnosis more than 4 weeks before diagnosis not known no yes , in
(place)
ALL treatment started at another department:
DIAGNOSIS:
Date of diagnosis: Type of diagnosis: BM at diagnosis: Primary disease
(dd/mm/yyyy)
Secondary malignancy
Relapse
central review in local review (to be confirmed by reference lab) Blasts in BM (%): Comments:
CBC at diagnosis:
WBC / L: Platelets / L: Blasts (%): Hb (g/dL): . cm BSA: . m2
Weight:
kg
Height:
Date of 1. prednisone dose:
(dd/mm/yyyy)
1/3
ALL IC-BFM 2002
Appendix 1.1
CNS LEUKEMIA (initial):

Blasts in CSF: CSF contaminated with blood: Cranial nerve palsy:
no no no no
yes yes yes yes
Cerebral mass: Retinal involvement: Cells in CSF / L: Blasts in CSF (%):
no no
yes yes
CNS status at diagnosis:

1 2 3
ORGAN INVOLVEMENT (initial):

Hepatomegaly: Splenomegaly: Thymus / Mediastinum: Testicles / Ovaries: Other organ involvement: no no no no yes: yes: yes yes cm below costal margin cm below costal margin
DIAGNOSTICS:
Immunology: no yes, central in yes, local (please add copy) no yes, central in yes, local (please add copy) no yes, central in yes, local (please add copy) Result:
DNA index:
DNA index:
Cytogenetics:
Result:
Molecular (cyto)genetics: BCR/ABL TEL/AML1 MLL/AF4 no yes, performed in no yes, performed in no yes, performed in
pos. neg. non-evaluable
Result: Result: Result: 2/3
ALL IC-BFM 2002
Initial-Response Form
Date:
Appendix 1.1
DAY 8 prednisone response:

PB:
(dd/mm/yyyy)
no (not performed), reason: yes, central review in yes, local review (to be confirmed by reference lab) WBC / L: Blasts in PB (%): Pre-phase cumulative dose of prednisone (7 days): mg/m2 Blast cell count / L:
BM (optional):
no (not performed) yes, central review in yes, local review (to be confirmed by reference lab) Normal Hypoplastic Aplastic Blasts in BM (%): Comments:
BM cellularity:
DAY 15:
PB + BM:
Date:
(dd/mm/yyyy)
no (not performed), reason: yes, central review in yes, local review (to be confirmed by reference lab) Blast cell count / L: Normal Blasts in BM (%): Hypoplastic Comments: Aplastic
(dd/mm/yyyy)
WBC / L: BM cellularity:
DAY 33:
PB + BM:
Date:
no (not performed), reason: yes, central review in yes, local review (to be confirmed by reference lab)
Blast cell count / L: BM cellularity:
Normal Hypoplastic Aplastic no
Blasts in BM (%): Comments:
CR 1 achieved: Comments:
yes
If no, date of CR 1:
(dd/mm/yyyy)
Patient alive Patient dead

Physician Date (dd/mm/yyyy) Signature
Please send copy to National Study Coordinator
3/3
ALL IC-BFM 2002
Appendix 1.2
ALL IC BFM 2002

Follow-up Form
National Study Coordinator: Address: Tel.: Fax: Initials (Family name/First name) / Risk group: SR-1 SR-2 IR-1 IR-2 UPN Center Sex (M/F) Date of Birth (dd/mm/yyyy)
HR-1 HR-2A HR-2B Date: Testicles yes Date: Date: B-ALL CNS tumor Other:
(dd/mm/yyyy) (dd/mm/yyyy)
RELAPSE:
1.
2. BM
3.
Relapse CNS
Site of relapse: Remission achieved:
no
SECONDARY MALIGNANCY:
Type of secondary malignancy: ALL HD Other:
(dd/mm/yyyy)
AML other tumor
NHL
LATE TOXICITY:
Site/Type:
Date: Psychologic Sense organ Lungs Endocrine Hematologic GIT Skin Osteonecrosis Osteoporosis Other:
(dd/mm/yyyy)
(dd/mm/yyyy)
Skeleton Heart CNS Kidney Liver Date of death:
Patient dead:
Autopsy:
no
yes
Cause of death: Death in induction Death in CR SCT Follow - up: Date of last follow-up: Phase of protocol: Comments:
Relapse Secondary malignancy Other:

(dd/mm/yyyy)
Physician
Date (dd/mm/yyyy)
Signature
Please send copy to National Study Coordinator
Appendix 1.3
VARIABLES IN ALL IC-BFM 2002 DATABASE

In this database the data of all children diagnosed with ALL and entered into the ALL ICBFM 2002 trial will be pooled regardless of whether they are observed or protocol patients. Each group will provide the data according to the variable names and codes listed bellow, and the Trial Statistics Center will produce, based on them, the pooled database. The type of file can be SAS, ACCESS or DBF. Appendix 1.3 is composed of 5 parts: Appendix 1.3.a through Appendix 1.3.e: Appendix 1.3.a
1. Baseline Variables UPN Group
Baseline Data
VAR. NAME UPN GROUP Code Use your own UPN 1-Chile, 2-Argentina, 3-Uruguay, 4-Czech Republic, 5-Hungary, 6-Poland, 7-Israel, 8-Hong Kong, 9-Croatia, 10-Yugoslavia, 11-Turkey, 12-Ukraine, 13-Cuba First letter Family name, First name 1=male, 2=female day/month/year day/month/year no=1(observed pt), yes=2(protocol pt)
Initials Sex Date of birth Date of diagnosis Eligible for study Reason for ELIG=No
INIT SEX DOB DOD ELIG CONOELIG
1=conditions for participation in study not fulfilled (e.g. age of the patient) 2=preexisting disease/ALL is second malignancy 3=significant previous treatment 4=essential data missing (no safe diagnosis a./o. therapy branch stratification possible)
(kg) (cm) (m2) 1=no, 2=yes 1=within 4 weeks before diagnosis 2=more than 4 weeks before diagnosis 9= not known
Weight Height Body surface Previous treatment with Corticosteroids or cytostatic agents Previous treatment timing WBC at diagnosis (/L) % blasts (PB) % BM blasts at diagnosis Platelets (/L) Hb (g/dl) CNS status Cells in CSF (/L) Blasts in CSF (%) CSF contaminated with blood Cerebral mass Cranial nerve palsy
WEIGHT HEIGHT BS PRETX PRETIME WBC BLA BM PLT HB CNS CSF_CELL BLA_CSF CM_INV CNP_INV
1=CNS status 1 2=CNS status 2 3=CNS status 3 1=no, 2=yes, 9=no data 1=no, 2=yes, 9=no data 1=no, 2=yes, 9=no data
Splenomegaly Splenomegaly Hepatomegaly Hepatomegaly Mediastinal mass Testicular involvement Karyotype t(4;11) Karyotype t(9;22) Other karyotypes 1 Other karyotypes 2 Hyper-/Hypodiploidy BCR/ABL MLL/AF4 TEL/AML1 Immunophenotype
SPL_INV MEA_SPLE HEP_INV MEA_LIV MED_INV GON_INV T411 T922 KARYO1 KARYO2 HYPDIP BCR MLL TEL IMMPHEN
TCR alpha/beta (required only if IMMPHEN = 4 or 5) TCR gamma/delta (required only if IMMPHEN = 4 or 5) AHL-Type (required only if IMMPHEN = 12) Markers (percent positive cells in blast gate) CD7 CD2 CyCD3 Surface CD3 CD19 CD10 CD33 CD66c DNA index WBC/L on day 8 Blast cell count/L on day 8 WBC/L on day 15 Blast cell count/L on day 15 BM day 8, % blasts BM day 15, % blasts BM day 33, % blasts
TCRA TCRB AHLT
1=no, 2=yes, 9=no data cm below costal margin 1=no, 2=yes, 9=no data cm below costal margin 1=no, 2=yes, 9=no data 1=no, 2=yes, 9=no data 1=negative, 2=positive, 9=no data 1=negative, 2=positive, 9=no data See code list cytogenetics See code list cytogenetics 1= <45 2=>50 1=negative, 2=positive, 9=no data 1=negative, 2=positive, 9=no data 1=negative, 2=positive, 9=no data 1=Pro-T 2=Pre-T 3=Intermediate (cortical) T 4=Mature T 5=T-lineage not classified 6= Pro-B 7= Common 8=Pre-B 9=Mature B 10=B-lineage not classified 11=AUL 12=AHL 99=no data 1=negative, 2=positive 9=no data 1=negative, 2=positive 9=no data 1=b-lineage, 2=t-lineage
CD7 CD2 CYCD3 CD3 CD19 CD10 CD33 CD66C DNAI WBC_8 COBLA_8 WBC_15 COBLA_15 BLA_8 BLA_15 BLA_33
% % % % % % % %
Appendix 1.3.b Therapy 2. Therapy Data Date of start of treatment Pre-phase cumulative dose of prednisone (mg/m2) Date of first IT-MTX Dose of HD-MTX CR1 achieved Date of first complete remission Timing of CR1 Date of start of maintenance Date of end of treatment Radiotherapy Risk group Date of randomization Treatment assigned Treatment administered Cause of non-randomization Cause of shift (if treatment administered differs from assigned)
VAR. NAME
Code
DOSTR PDN_DOSE DOMTX HD_MTX CR1 DOCR1 CR_PHASE DOSM CHTEND RT RG DORAND R_ASS R_ADM CONORAN COSHIFT
day/month/year day/month/year 1=2g/m2, 2=5g/m2 1=no, 2=yes day/month/year 1=early (day 33), 2=late (>day 33) day/month/year day/month/year 1=no, 2=yes 1=SR, 2=IR, 3=HR day/month/year 1=SR-1, 2=SR-2, 3=IR-1, 4=IR-2, 5=HR-1, 6=HR-2A, 7=HR-2B 1=SR-1, 2=SR-2, 3=IR-1, 4=IR-2, 5=HR-1, 6=HR-2A, 7=HR-2B 1=clinical decision, 2=parent's refusal of random, 3=error, 9=not known 1=doctor refuses the arm, 2=parents refuse the arm, 9=not known
Appendix 1.3.c
Therapy Realization & Toxicity

VAR. NAME UPN GROUP Code use your own UPN 1 Chile, 2 Argentina, 3-Uruguay, 4-Czech Republic, 5-Hungary, 6-Poland, 7-Israel, 8-Hong Kong, 9-Croatia, 10-Yugoslavia, 11-Turkey, 12-Ukraine, 13-Cuba 1=Protocol I, 2= Protocol I', 3=Protocol mM, 4=Protokol M, 5=Protocol II, 6= Protocol III, 7= HR-1', 8=HR-2', 9=HR-3' Prot- II/III 1=1., 2= 2. 3=3. HR: 1=Block no 1 ...6=Block no 6 Prot I/II/III 1=phase 1, 2=phase 2 Prot M. 1 = 1.MTX, 2 = 2.MTX, ...
3. Therapy-Flow & Toxicity Data UPN Group
Treatment element
ID_ELE
Element no Element phase First day of the element Last day of the element Body surface (m2) Deviations in timing Deviations in medication (replacement of drugs) Deviation in dosages
ELE_NO ELE_PH ELESTART ELEEND BS DEV_TIM DEV_MED DEV_DOS
day/month/year day/month/year
1=no, 2=yes 1=no, 2=yes 1=no, 2=yes
Deviation: cause Deviation: Description and cause General condition Infection Fever Nausea Vomiting Stomatitis Diarrhea S- bilirubin S- ALT/ S- AST Creatinine Proteinuria Hematuria Creatinine clearance Arrhythmia Cardiac function Echocardio: LV-SF Central neurotoxicity Peripheral neurotoxicity Osteonecrosis Other toxicity Notes/other complications
DEV_CAU DEV_NOTE TX_GC TX_INF TX_FEV TX_NAUS TX_VOM TX_STOM TX_DIAR TX_BILI TX_ALT TX_CREA TX_PROT TX_HEMA TX_CRCL TX_ARRH TX_CARD TX_SG TX_CNEU TX_PNEU TX_OST TX_OTH TX_NOTE
1=initial complications, 2=allergic reaction 3=other toxicity, 4=relapse/death 4=other NCI Grade 0-4, 9 = no data NCI Grade 0-4, 9 = no data NCI Grade 0-4, 9 = no data NCI Grade 0-4, 9 = no data NCI Grade 0-4, 9 = no data NCI Grade 0-4, 9 = no data NCI Grade 0-4, 9 = no data NCI Grade 0-4, 9 = no data NCI Grade 0-4, 9 = no data NCI Grade 0-4, 9 = no data NCI Grade 0-4, 9 = no data NCI Grade 0-4, 9 = no data NCI Grade 0-4, 9 = no data NCI Grade 0-4, 9 = no data NCI Grade 0-4, 9 = no data NCI Grade 0-4, 9 = no data NCI Grade 0-4, 9 = no data NCI Grade 0-4, 9 = no data NCI Grade 0-4, 9 = no data 1=no, 2=yes Other toxicity, description; Notes
Appendix 1.3.d FU 4. FU Data Date of first relapse Site of relapse: BM Site of relapse: CNS Site of relapse: Testis Site of relapse: Other Date of death Cause of death
VAR. NAME DOREL R_BM R_CNS R_TESTIS R_OTHER DODEAD CODEAD
Code
Phase of death Date of 2nd malignancy Type of 2nd malignancy Date of last follow-up
PH_DEAD DOSMN T_SMN DOLFU
day/month/year 1=no, 2=yes 1=no, 2=yes 1=no, 2=yes 1=no, 2=yes day/month/year 1=progressive ALL, 2=SCT-related, 3=2nd tumor, 4=sepsis, 5=pneumonia, 6=other infection, 7=hemorrhage, 8=MOF, 9=other (specify), 99=not known 1=before start of therapy, 2=in induction before CR, 3=in first CR, 4=after relapse, 5=after 2nd tumor day/month/year Text (C 20) day/month/year
Appendix 1.3.e SCT 5. SCT Data Eligible for SCT Search for donor No of siblings Histocompatibility Date of HLA typing Date of SCT Phase of disease at Tx Type of SCT
VAR. NAME ELBMT DONOR SIBL HISTO DOHLA DOBMT PBMT TBMT
Code
1=no, 2=yes, 9=not known 1=no, 2=yes, 9=not known 1=no, 2=yes, 9=not known day/month/year day/month/year 1=in CR1, 2=not in CR (e.g. nonresponder) 1=matched sibling donor 2=matched family donor other than sibling 3=mismatched family donor 4=matched unrelated donor 5=mismatched unrelated donor 6=syngeneic 9=not known 1=BM, 2=PBSC, 3=cord blood, 9=not known
Source of the graft
SBMT
Addendum 1.3
CODE LIST CYTOGENETICS

a la J. Harbott (Some codes are relevant only for AML or lymphoma) -1 0 1 2 3 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 31 32 33 34 35 36 37 50 51 52 53 54 55 60 61 62 no data no result normal t(9;22)(q34;11) 11q23 aberrations der(1q) single-cell aberrations t(1;19)(q23;p13) t(4;11)(q21;q23) t(8;14)(q24;q32), t(2;8), t(8;22) 14q11 aberrations del(6q) del(9p) der(12p) >50 t(11;19)(q23;p13) t(12;21)(p13;q22) t(8;21)(q22;q22) t(15;17)(q22;q11) inv(16)/t(16;16) t(9;11)(p22;q23) t(6;9)(p23;q34) der(3q) +4 +8 -5/5q-X/-Y +12 i(17q) t(1;22)(p13;q13) complex 7p+21 7 (in general) -7 (only) -7 (+ additional) 7q- (only) 7q- (+ additional) -7 unclear; e.g. +mar 1p 2p12 t(2;5)
except t(4;11),t(11;19), t(9;11)
>=3 aberrations
63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 99
der(3)(q27) +7 der(7)(p22) der(7)(q34~35) 8q24 del(10q) t(11;14)(q13;q32) / der(11)(q13) t(11;18) Dup(12q) del(13q) del(14q) t(14;18)(q32;q21) der(14q32) der(15q) der(17p) der(17q) +18 der(18q) der(22)(q11) +X der(2)(p23) der(5)(q35) t(5;14)(q35;q32) random aberration
other than code 13
except Ph+ except t(2;5) except t(2;5) not in this list
Appendix 1.4
ALL IC-BFM 2002 Severe-Adverse-Event Form

Report every unexpected toxic event of grade 3 and 4
except hematologic toxicity, infection and mucositis
Pt Initials:
Surname:____________ Name:___________ Date of birth:____________
Event and related measures description: ___________________________________________________________________________ ___________________________________________________________________________ ___________________________________________________________________________ ___________________________________________________________________________ Grade of toxicity according to NCI Common Toxicity Criteria: Event: onset: __________ end: __________ 3 4
or continuation
Cause of event Is the initial status of the patient or other disease responsible for this event? yes probably possibly improbably no impossible to consider Is there any relation between the event and a study medication? yes probably possibly improbably no impossible to consider Course of event Death Autopsy performed yes no Cause of death: primary disease complications of treatment other _____________ life-threatening event persistent or severe sequels necessity or prolongation of hospitalization Send this form by fax to your national study coordinator & national data manager. Fax: Fax: Notes:
Date:________________
Signature:________________
APPENDIX 2
PATIENT / PARENT INFORMATION & CONSENT
2.0 2.1 2.2 Patient & Parent Information Informed Consent Discussion Protocol on Therapy According to ALL IC-BFM 2002
2.3 Informed Consent with Randomization to Arm SR-1 & SR-2

2.4 2.5 2.6 Informed Consent with Randomization to Arm IR-1 & IR-2 Informed Consent with Randomization to Arm HR-1 & HR-2A Informed Consent with randomization to Arm HR-1 & HR-2B
Appendix 2.0 PATIENT & PARENT INFORMATION The treatment and its side effects must be explained to the patient and his/her parents or legal representatives prior to starting it. This study requires to inform on its meaning and the scientific progress achieved in the field of treatment of childhood leukemia. It is also required that the patient (whenever possible) and/or parents/legal guardians be informed on their right to refuse the study, withdraw from it at any time or select themselves the randomization arm during the course of therapy, and that they can do so without giving any cause, and be assured their decision is free, will not negatively affect the attitude of the staff to them, nor it will influence their right to opt for an alternative treatment. The previous study ALL-BFM 95, which, compared with other international studies, achieved a high percentage of first remission without significant increase in toxicity can serve as an alternative. The long-term results as well as the possible late side effects of that study are not yet known, however. The radiation oncologist clarifies radiation therapy and its side effects. With regard to any possible surgical intervention the responsibility to inform lies with the surgeon and the anesthesiologist performing the procedure. According to the World Medical Association (WMA) Declaration of Helsinki, first adopted by the 18th WMA General Assembly (GA) in Helsinki, Finland, June 1964, and amended by 5 subsequent WMA GAs, last by the 52nd WMA GA in Edinburgh, Scotland, October 2000, it is required that younger patients be informed and asked permission to treat, so far as they are able to understand the meaning, purpose and risks of the proposed therapy, and to make their will clear. This requirement holds also for this study. Whether this step is appropriate, must be judged in each individual case. The same approach should be used with adolescent patients between 14 and 18 years of age who are informed on their disease. The treating physician upon discussion with the parent(s)/legal representative(s) will decide as to whether explanation of the study to their adolescent child is appropriate, and if an informed consent should/could be obtained from him/her. Informing a child should be done in a manner corresponding to his/her age and in the presence of the parent(s)/legal guardian(s). If the patient reaches the age of 18 years in the course of the study, his/her consent to continue on it should be obtained. The study recommends the patient (if deemed competent) and legal representative(s) sign the consent, in which the content of the informing discussion is documented. In addition, it is recommended to give them a copy of the whole protocol they have just signed. It is however recognized that these issues will depend on the national conditions, i.e. culture, traditions, legislation, etc. Therefore, informed verbal consent is also acceptable, provided it is clearly and adequately documented and signed by the physician in charge and two witnesses. A copy of the signed written informed consent or a statement regarding a verbally obtained informed consent must be sent to the national data manager. All personal data necessary for central documentation, analysis and reporting of the results will be blinded by the use of numbers. Following an in-depth discussion, the members of the Trial Management Committee (TMC) and Trial Steering Committee (TSC) approved the therapeutic protocol ALL IC-BFM 2002, and expressed their readiness to perform all the tasks required by this study. The Ethics Committees (Institutional Review Boards) of the participating countries/centers examined the ethical and legal issues related to the study and raised no objection against the concept and conduct of the trial or the current form of the protocol.
Appendix 2.1 INFORMED CONSENT with therapy of acute lymphoblastic leukemia according to ALL IC-BFM 2002 Study Patient: Date of birth:.. (Name) Date of informing discussion: Informing physician:.. (Name and appointment) I confirm that the above named physician has informed me today on my/my child's illness and of the proposed therapy. I know that without appropriate therapy this disease cannot be controlled. I am informed on the chances for success with the proposed therapy and on other formerly proven therapies for this disease. Treatment should proceed according to the study ALL IC-BFM 2002, in which more than 10 countries participate. Approximately 1,000 patients are treated according to this study annually, with the total number of patients reaching 4,000 by the end of accrual. The goal of the study is to increase the cure rate by adjusting treatment to the risk of relapse in each patient. The risk of treatment failure, when the disease cannot be controlled with available therapy, as well as the risk of relapse, i.e. recurrence after initial disappearance of the disease (remission) are determined by different biologic properties of the leukemic cells and their response to therapy. In this study, the early treatment response as evaluated in blood on day 8 and in bone marrow on day 15 and 33 serves to divide patients into risk groups requiring different therapy. I understand that in this way the intensity of therapy can be adjusted to the individual risk of relapse. The difference from other therapeutic trials and the basis of modern clinical research has been explained to me. The treatment is primarily based on the use of medications that kill leukemic cells, i.e. chemotherapy. A small number of patients should also receive radiation therapy to the brain and/or testicles, which are involved by leukemia, or if the risk of relapse within the central nervous system is considered to be high. Chemotherapy is divided into sequential therapeutic blocks, each using a combination of drugs with different antileukemic properties. Combining a number of different chemotherapeutic agents (cytostatics) should decrease the risk of developing resistance to therapy by leukemic cells. The side effects and risks of therapy were explained to me in detail. These include nausea and vomiting, transient hair loss, damage to mucous membranes, suppressed bone marrow function and blood-forming elements with increased risk of infection or bleeding, and possible delayed side effects such as damage to organs, possible infertility, need for control of childbearing and risk of late-appearing serious illnesses including, among others, second malignant tumors. The reason for radiation therapy in a small number of patients is destruction of leukemic cells in the central nervous system and the testicles. Possible late side effects of this therapeutic modality were explained to me. The radiation therapist will provide more detailed information on radiation therapy to me before starting that treatment. If the initial response to therapy is inadequate, the intensity of therapy must be increased. In a small number of patients with a high risk of relapse, bone marrow transplantation is indicated, so far as a suitable donor is available. If this is a case with me/my child, further information regarding the risks and chances of this procedure and of alternative methods will be provided to me/my child. I will then have the opportunity to decide on that option.
Patients will be assigned to one of three risk groups based on the results of risk assessment, i.e. response to prednisone; response to multi-agent chemotherapy and biologic markers, as these become known during the first one to three months of therapy: SR = standard risk; IR = intermediate risk; HR = high risk. In the SR & IR groups, during the last intensive part of therapy (reinduction), Protocol III will be tested in a random manner in some patients (experimental arm) against Protocol II in others (control arm). In the HR group, Protocol III will be similarly tested either against Protocol II (option HR-2A, as known from the AIEOP LLA-95 trial) or against so-called HR therapy blocks plus Protocol II (option HR-2B, which is essentially the same as in the ALL-BFM 95 study). Protocol III is a shortened version of Protocol II. Allocation of the patients into one or the other arm will be done by randomization, i.e. by chance and anonymous selection, which will be performed by the national study center following my agreement with this manner of patient selection. Randomization is necessary to ensure equal numbers of patients be assigned in each arm for valid scientific analysis. I will be informed about the result of randomization for me/my child. I also have the right to refuse this result and choose myself one of the alternative therapeutic arms or opt for another established treatment. The ALL IC-BFM 2002 study contains two research projects that will assess minimal residual disease (MRD). A small amount of blood (5 ml) and/or bone marrow (2 ml or exceptionally 10 ml) will be obtained for this purpose from me/my child on day 8, day 15 and 33 in Protocol I/I', before consolidation and possibly two years following the diagnosis. Evaluation of MRD will be performed in the national reference laboratories, where only samples of blood and/or bone marrow will be submitted. The research results will not be disclosed to the treating center or to the patient/legal representative(s), as the meaning of these results for each individual patient will be evaluated only during the course of the study, and hence cannot have direct implications with regard to the treatment being given to him/her. I know that at the same time bone marrow smears are looked at in the microscope in order to assess the rate at which malignant cells are cleared by counting their percentage, thus providing a precise estimate of the efficiency of the already delivered chemotherapy. The morphologic findings of bone marrow smears worked out day 15, day 33 of Protocol I/I', and before consolidation do have direct therapeutic implications and prognostic value for me/my child. On the other hand, I know that although bone marrow smears from day 8, and 2 years following diagnosis (if any) will be also evaluated similarly, the morphologic findings at those time points will have no impact on decision-making with regard to treatment, and these specimens will serve solely for scientific research on MRD. However, I will be free to make the decision as to whether I/my child will participate in these research projects. I/my child will be acknowledged of any important new findings, changes or amendments related to me/my child by the physician in charge who will be notified in a written form by the TMC/TSC of this study or be informed at a meeting of the I-BFM-SG. The treating physician is responsible for informing me/my child on these issues in a way I/my child can understand. I am aware that progress in the management of leukemia is possible only through cooperation of many dedicated pediatric hematology/oncology centers. This requires transmission of patients' data to the national data management center, the Trial Statistics Center (central database) and the national reference and research labs involved in this trial. I understand that I can refuse transmission of any personal data or data related to me/my child without stating the reason and without consequences to my child or me. Publication of the results of this study will employ anonymous data only. Therefore it is not possible to identify any individual patient retrospectively. I understand that treatment will proceed according to ALL IC-BFM 2002 study, which was explained to me/my child. I also understand that I can recall my consent to this study or
certain parts of it at any time and select a different type of therapy of proven efficacy. The recall of my agreement can be done informally. I feel I was adequately informed and have no further questions. _______________________ Place _______________________ Patient Name _______________________ Name of legal representative _______________________ Name of physician _______________________ Name of a witness ____________________________ Signature Date ____________________________ Signature Date ____________________________ Signature Date ____________________________ Signature Date
A copy of this Informed Consent and a scheme of the planned therapy should be given to the patient and/or parent(s)/guardian(s). A copy of this Informed Consent is attached to the patient's file at the treating center. Another copy should be sent to the national data manager, but no copy is required by the Trial Statistics Center (central database).
Appendix 2.2
DISCUSSION PROTOCOL ON THERAPY ACCORDING TO ALL IC-BFM 2002

Treatment of Acute Lymphoblastic Leukemia in Children & Adolescents According to ALL IC-BFM 2002 Therapy Plan
(to remain in the patient's file)
_______________________________ Patient's name
_____________________ Date of birth
Informing discussion was held at________________________________________ Participants: ( ) ( ) ( ) ( ) Legal representative(s)____________________________ Patient_________________________________________ Physician_______________________________________ Witness________________________________________ Information given includes: ( ) ( ) ( ) ( ) ( ) Diagnosis Prognosis without appropriate therapy Expected prognosis with therapy according to ALL IC-BFM 2002 study Prognosis with alternative therapy (for example ALL-BFM 95, ALL-BFM 90) Effects of chemotherapy: Destruction of leukemic cells with subsequent restoration of normal function of bone marrow, need for intensive combined therapy with multiple cytotoxic drugs, need for repetition of therapeutic blocks in certain risk groups Side effects of chemotherapy: Nausea and vomiting, temporary hair loss, transient damage to mucous membranes, tissue necrosis (especially following DOX, DNR, VCR, VDS), temporary impairment or failure of normal production of blood elements, increased susceptibility to infection, organ dysfunction and possible organ damage (liver, pancreas, stomach and bowels, kidneys, urinary tract, heart, lungs, nervous system, etc), possibility of infertility, bone necrosis, risk of second malignancy Effects of radiation therapy: Destruction of leukemic cells dwelling in the brain and meninges with subsequent decrease in the risk of relapse in certain subgroups of patients
( )
( )
Destruction of leukemic cells within the testicles that may persist in spite of delivered or ongoing chemotherapy ( ) Side effects of radiation therapy: Apathy/somnolence syndrome, headache, transient increase in intracranial pressure, possible intellectual deficits and other late side effects Adjuvant studies: Research projects on MRD, exchange of data from adjuvant studies Aims, basis & structure of the study: ( ) Meaning of the study: Improvement in prognosis for children with acute lymphoblastic leukemia, especially for those with inadequate response to initial therapy Knowledge based on scientific progress Randomization in all three risk groups (SR, IR, HR) Anonymous and confidential storage, sharing and analysis of patient data Freedom to choose randomization arm or other proven therapy by patient/legal representative(s) Points not crossed were not discussed for the following reason: ( ) ( ) ( ) Refusal by patient Refusal by legal representative(s) Risk to patient Decision: ( ) ( ) Participate in study Not participate in study
( )
( ) ( ) ( ) ( )
Date: ____________________________ Informing physician: ________________________________________ Witness: __________________________________________________ Patient/Legal representative(s): ________________________________
Appendix 2.3 INFORMED CONSENT WITH RANDOMIZATION TO ARM SR-1 & SR-2 for patients in the standard-risk group: SR
Patient: Date of birth: ... Progress in treatment of malignant diseases of childhood has been made predominantly through so-called randomized clinical trials/studies. Randomized study means that a certain part of therapy or the entire therapy is provided in two different versions (A and B), whereby one half of the patients receive therapy A and the other half therapy B. Which therapy will be assigned to each individual patient is decided by a computer program in the study center on the basis of chance selection (randomization). In order to determine whether therapies A and B are equivalent or whether one of them offers some advantage it is essential to compare a large number of patients, who have similar baseline characteristics and conditions. Patients in the SR group will be randomized to receive either one of two therapeutic approaches that differ as follows: In the SR-1 arm Protocol II will be given only once, while in the SR-2 arm Protocol III will be used twice with a 12-week interval in between. In Protocol III dexamethasone is used for 23 days instead of 30 days in Protocol II. By repeating Protocol III (SR-2) the total dose of dexamethasone will increase by more than 40%. Three drugs (vincristine, doxorubicin and asparaginase) are used from day 1 in Protocol III, and from day 8 in Protocol II. This means it will take 28 days for Protocol III to complete against 49 days for Protocol II. Only two doses each of vincristine and doxorubicin are used in Protocol III. Through repeating Protocol III, patients assigned to SR-2 arm will receive twice the total dose of asparaginase, cytarabine and thioguanine, compared to those allocated to SR-1 arm, but the total dose of vincristine, doxorubicin and cyclophosphamide will remain the same in both arms. Between the first and second Protocol III there is an interval of 12 weeks, during which the patients will receive a 10-week course of daily 6-mercaptopurine and weekly methotrexate, both by mouth. This course of so-called interim maintenance therapy begins 1 week after the first Protocol III and ends up also 1 week before the second one. Maintenance therapy follows the second Protocol III in SR-2 arm and the single Protocol II in SR-1 arm and lasts for both arms until week 104 from diagnosis (start of treatment). With this longer and more intensive therapy in SR-2 arm it is hoped to improve the chances for cure, but an increase in complications is also expected. However, whether this is indeed the case can be definitively determined only on final evaluation of the study. Based on the current state of knowledge a substantial difference in management risks between these two therapeutic alternatives is not expected. According to the general principles valid for the conduct of such studies like ALL IC-BFM 2002, the legal representative(s) and/or the patient must be informed about randomization and their consent obtained. By your signature you confirm you were informed about: 1. 2. 3. ( ) ( ) Place Date Purpose and goal of randomization Therapeutic approach assigned to your child/yourself by randomization Possibility to refuse randomization and select an alternative therapy yourself Consent for randomization given Consent for randomization not given ________________________________________ ________________________________________ ________________ Informing physician ________________ Witness
Signatures ______________________________ Legal representative(s) and/or patient
(This form should be kept in the patient's file at the treating center. The national data manager should be only notified of the consent, using the form enclosed with a letter from him/her telling the result of randomization, i.e. the arm assigned to the patient)
Appendix 2.4 INFORMED CONSENT WITH RANDOMIZATION TO ARM IR-1 & IR-2 for patients in the intermediate-risk group: IR
Patient: Date of birth: ... Progress in treatment of malignant diseases of childhood has been made predominantly through so-called randomized clinical trials/studies. Randomized study means that a certain part of therapy or the entire therapy is provided in two different versions (A and B), whereby one half of the patients receive therapy A and the other half therapy B. Which therapy will be assigned to each individual patient is decided by a computer program in the study center on the basis of chance selection (randomization). In order to determine whether therapies A and B are equivalent or whether one of them offers some advantage it is essential to compare a large number of patients, who have similar baseline characteristics and conditions. Patients in the IR group will be randomized to receive either one of two therapeutic approaches that differ as follows: In the IR-1 arm Protocol II will be given only once, while in the IR-2 arm Protocol III will be used thrice with 6-week intervals in between. In Protocol III dexamethasone is used for 23 days instead of 30 days in Protocol II. By repeating Protocol III (IR-2) the total dose of dexamethasone will increase by about 111%. Three drugs (vincristine, doxorubicin and asparaginase) are used from day 1 in Protocol III, and from day 8 in Protocol II. This means it will take 28 days for Protocol III to complete against 49 days for Protocol II. Only two doses each of vincristine and doxorubicin are used in Protocol III. Through repeating Protocol III, patients assigned to IR-2 arm will receive 3-fold the total dose of asparaginase, cytarabine and thioguanine, and 1.5-fold the total dose of vincristine, doxorubicin and cyclophosphamide, compared to those allocated to IR-1 arm. Between the individual Protocols III there is an interval of 6 weeks, during which the patients will receive a 4-week course of daily 6-mercaptopurine and weekly methotrexate, both by mouth. This course of so-called interim maintenance therapy begins 1 week after the previous Protocol III and ends up also 1 week before the subsequent one. Two courses of interim maintenance therapy will be given to patients in IR-2 arm. Maintenance therapy follows the third Protocol III in IR-2 arm and the single Protocol II in IR-1 arm and lasts for both arms until week 104 from diagnosis (start of treatment). With this longer and more intensive therapy in IR-2 arm it is hoped to improve the chances for cure, but an increase in complications is also expected. However, whether this is indeed the case can be definitively determined only on final evaluation of the study. Based on the current state of knowledge a substantial difference in management risks between these two therapeutic alternatives is not expected. According to the general principles valid for the conduct of such studies like ALL IC-BFM 2002, the legal representative(s) and/or the patient must be informed about randomization and their consent obtained. By your signature you confirm you were informed about: 1. 2. 3. ( ) ( ) Place Date Purpose and goal of randomization Therapeutic approach assigned to your child/yourself by randomization Possibility to refuse randomization and select an alternative therapy yourself Consent for randomization given Consent for randomization not given ________________________________________ ________________________________________ ________________ Informing physician ________________ Witness
Appendix 2.5 INFORMED CONSENT WITH RANDOMIZATION TO ARM HR-1 & HR-2A for patients in the high-risk group: HR
Patient: Date of birth: ... Progress in treatment of malignant diseases of childhood has been made predominantly through so-called randomized clinical trials/studies. Randomized study means that a certain part of therapy or the entire therapy is provided in two different versions (A and B), whereby one half of the patients receive therapy A and the other half therapy B. Which therapy will be assigned to each individual patient is decided by a computer program in the study center on the basis of chance selection (randomization). In order to determine whether therapies A and B are equivalent or whether one of them offers some advantage it is essential to compare a large number of patients, who have similar baseline characteristics and conditions. For patients in the HR group, two reinduction approaches of comparable efficacy are available: the AIEOP (Italian) option and the BFM (German) option. Either may serve as the control arm designated HR-2A and HR2B, respectively. Each national group/center participating in this trial is free to choose one of those options according to its previous experience, i.e. this is not done by randomization. Our national study group/center has opted for HR-2A as the control arm, against which the experimental arm (HR-1) will be tested in a randomized manner. Patients in the HR group will be randomized to receive one of two therapeutic approaches: either triple Protocol III and two 4-week phases of so-called interim maintenance therapy for HR-1, or double Protocol II and a single 4-week phase of interim maintenance therapy for HR-2A. Protocol II & Protocol III are intensive therapy elements, between which 1-week rest periods and courses of less intensive interim maintenance treatment with daily 6-mercaptopurine and weekly methotrexate, both given by mouth, are inserted. The overall duration of reinduction therapy including the rest breaks necessary for recovery of bone marrow function is 24 weeks in arm HR-1 and 20 weeks in arm HR-2A. The same drugs are employed in both arms, however over somewhat different time schedules and/or at variable dosages with regard to the number of doses, the length of treatment and exceptionally the dose size (cyclophosphamide). HR-1 differs from HR-2A in that it contains 25% less vincristine, doxorubicin and cyclophosphamide, but approximately 25 mg/m2 more dexamethasone, 50% more asparaginase, 6-thioguanine and cytarabine, and 100% more 6-mercaptopurine and methotrexate. In addition, depending on whether the central nervous system was/was not involved by leukemia at the beginning, i.e. at the time of initial diagnosis, patients allocated to arm HR-1 will receive 9 or 6 doses of intrathecal methotrexate, whereas those in HR-2A will get 8 or 4 such doses of the drug. However, there is no difference in cranial radiotherapy between the two arms. Two weeks following reinduction therapy, all patients from both arms are put on maintenance therapy that continues until week 104 from diagnosis (start of treatment). With the changes in dosage, schedule and duration of late reintensification (reinduction) therapy introduced in HR-1 arm it is hoped to improve the chances for cure, but an increase in complications is also expected. However, whether this is indeed the case can be definitively determined only on final evaluation of the study. Based on the current state of knowledge a substantial difference in management risks between these two therapeutic alternatives is not expected, as all therapeutic elements used in this study have been employed in previous trials. According to the general principles valid for the conduct of such studies like ALL IC-BFM 2002, the legal representative(s) and/or the patient must be informed about randomization and their consent obtained. By your signature you confirm that you were informed about: 1. Purpose and goal of randomization 2. Therapeutic approach assigned to your child/yourself by randomization 3. Possibility to refuse randomization and select an alternative therapy yourself ( ) Consent for randomization given ( ) Consent for randomization not given Place ________________________________________ Date ________________________________________ Signatures ______________________________ ________________ ________________ Legal representative(s) and/or patient Informing physician Witness (This form should be kept in the patient's file at the treating center. The national data manager should be only notified of the consent, using the form enclosed with a letter from him/her telling the result of randomization, i.e. the arm assigned to the patient)
Appendix 2.6 INFORMED CONSENT WITH RANDOMIZATION TO ARM HR-1 & HR-2B for patients in the high-risk group: HR
Patient: Date of birth: ... Progress in treatment of malignant diseases of childhood has been made predominantly through so-called randomized clinical trials/studies. Randomized study means that a certain part of therapy or the entire therapy is provided in two different versions (A and B), whereby one half of the patients receive therapy A and the other half therapy B. Which therapy will be assigned to each individual patient is decided by a computer program in the study center on the basis of chance selection (randomization). In order to determine whether therapies A and B are equivalent or whether one of them offers some advantage it is essential to compare a large number of patients, who have similar baseline characteristics and conditions. For patients in the HR group, two reinduction approaches of comparable efficacy are available: the AIEOP (Italian) option and the BFM (German) option. Either may serve as the control arm designated HR-2A and HR2B, respectively. Each national group/center participating in this trial is free to choose one of those options according to its previous experience, i.e. this is not done by randomization. Our national study group/center has opted for HR-2B as the control arm, against which the experimental arm (HR-1) will be tested in a randomized manner. Patients allotted to arm HR-1 will receive x3 an intensive therapy element (Protocol III) over 4 weeks each and two 4-week courses of less intensive treatment (so-called interim maintenance therapy) with daily 6mercaptopurine and weekly methotrexate, both by mouth, during the 6-week intervals between Protocols III. The overall duration of reinduction therapy including the four 1-week rest periods separating Protocols III and phases of interim maintenance treatment is 24 weeks. Patients assigned to the control arm (HR-2B) will sequentially receive 3 short, but very intensive blocks in the same composition and order as was the case during consolidation, i.e. HR-1', HR-2' & HR-3', with recovery periods of about 2 weeks each interposing those blocks. Following an additional rest break of 3 weeks, these patients will receive once Protocol II over 7 weeks. Interim maintenance treatment is not a part of the reinduction therapy in arm HR-2B. To facilitate rapid recovery of bone marrow function and to maintain the concept of dose intensity, i.e. larger doses of cytostatic drugs delivered per unit of time, a growth factor for granulocytes (GCSF) will be given during the rest period following each HR block. The overall duration of reinduction therapy in HR-2B including the rest pauses is 17 weeks. Furthermore, there are differences between Protocol II and Protocol III. In the former vincristine, doxorubicin and asparaginase are given x4 each beginning by day 8, whereas in the latter vincristine and doxorubicin 2 doses each, and asparaginase in 4 doses are used beginning by day 1. Dexamethasone is administered full-dose for 21 days and 14 days in Protocol II and Protocol III, respectively, then tapered over 9 days in both. Cyclophosphamide is given at 1 g/m2 (Protocol II), but at 0.5 g/m2 (Protocol III). Finally, depending on whether the central nervous system was/was not involved at the time of initial diagnosis, patients randomized to arm HR-1 will receive 3 or 2 doses of intrathecal methotrexate per each Protocol III, i.e. a total of 9 or 6 injections. On the other hand, those patient randomized to arm HR-2B will go to get 4 or 3 tripledrug doses of intrathecal methotrexate, cytarabine and prednisone during the HR blocks, and 4 or 2 doses of intrathecal methotrexate during Protocol II, i.e. a total of 8 or 5 injections. However, with regard to cranial radiotherapy, the only difference lies in timing: while it is delivered after the first intensive therapy element (first Protocol III) in arm HR-1, it follows the last one (single Protocol II) in arm HR-2B. Two weeks after the end of all intensive chemotherapy, patients of either arm are started on maintenance therapy, which is continued until week 104 from diagnosis (start of treatment). With this prolonged intensive therapy in HR-1 arm it is hoped to improve the chances for cure, but an increase in complications is also expected. However, whether this is indeed the case can be definitively determined only on final evaluation of the study. Based on the current state of knowledge a substantial difference in management risks between these two therapeutic alternatives is not expected, as all the therapeutic elements used in this study have been already employed in previous trials. According to the general principles valid for the conduct of such studies like ALL IC-BFM 2002, the legal representative(s) and/or the patient must be informed about randomization and their consent obtained. By your signature you confirm that you were informed about: 1. 2. 3. Purpose and goal of randomization Therapeutic approach assigned to your child/yourself by randomization Possibility to refuse randomization and select an alternative therapy yourself
( ) ( ) Place Date
Consent for randomization given Consent for randomization not given ________________________________________ ________________________________________ ________________ Informing physician ________________ Witness
APPENDIX 3
3.0 3.0.a 3.0.b 1 3.0.b 1/1 3.0.b 2 3.0.b 2/1 3.0.b 1/2+2/2 3.0.c 1 3.0.c 1.1 3.0.c 2 3.0.c 2.1 3.0.d 3.0.d 1 3.0.d 2 3.0.e 3.0.e 1 3.0.e 2 3.0.f 3.0.f 1 3.0.g 3.0.g 1 3.0.h 3.0.h 1 3.0.i 3.1 3.2 3.2.a 3.2.b 3.3 Therapy Flow Sheets Global Therapy Scheme Protocol I Protocol I Infusion Plan / Phase 1 Protocol I' Protocol I' Infusion Plan / Phase 1 Protocol I/I' Infusion Plan / Phase 2 Protocol mM Protocol mM Infusion Plan Protocol M Protocol M Infusion Plan Protocol II Protocol II Infusion Plan / Phase 1 Protocol II Infusion Plan / Phase 2 Protocol III Protocol III Infusion Plan / Phase 1 Protocol III Infusion Plan / Phase 2 Block HR-1' Block HR-1' Infusion Plan Block HR-2' Block HR-2' Infusion Plan Block HR-3' Block HR-3' Infusion Plan Maintenance Therapy Leucovorin-Rescue Plan Therapy Toxicity Documentation Acute-Toxicity Form Acute-Toxicity Instructions Late-Effects Follow-Up Form
APPENDIX 3.0 THERAPY FLOW SHEETS
ALL IC-BFM 2002
ALL IC-BFM 2002

II
6-MP/MTX
12 Gy* only for T-ALL
Appendix 3.0.a
SR R
III
10-wk interim maintenance with 6-MP / MTX
dx
d15 d33
w12
III
6-MP/MTX
6-MP/MTX
II
I/I' **
12 Gy* only for T-ALL
mM$
IR
R
III
6-MP/MTX 4 wks 6-MP/MTX 4 wks
III
III
6-MP/MTX
HR: Allo-SCT# H R 3' AIEOP

12Gy*
12Gy*
PRED-PR IR, M3 d15 t(9;22) t(4;11) NR d33
H R 1'
H R 2'
II
H R 1' BFM H R 2'
6-MP/MTX 4 wks
II
H R 3'
6-MP/MTX
II
12Gy*
6-MP/MTX
10
12
52 104 W
BM sampling
IT MTX in maintenance therapy
** Prot. I' (DNR 30mg/m2 x2 only for SR patients with BCP-ALL)
BCP-ALL: MTX 2g/m2/24h x4; T-ALL: MTX 5g/m2/24h x4
* CNS status 1/2: pCRT = 12 Gy q 1.5 Gy per fraction CNS status 3: tCRT: 12/18 Gy q 1.5 per fraction dosage by age at treatment delivery Infants < 1 yr of age: neither pCRT nor tCRT See text for definition of CNS status, indications, timing & technique of CRT # Selected indications for allogeneic SCT in all strata of HR (See text) No randomization of AIEOP vs. BFM but choice by group according to previous experience with one of the two high-risk strategies in trial 95
ALL IC-BFM 2002
Appendix 3.0.b 1
Start Phase 1 Center:
Weight =
kg Height =
cm
ALL IC-BFM 2002: Protocol I

Date of Start: Date of End:
BSA =
m2
PRED mg
DOB:
p.o.
60 mg/m2/d =
Name:
VCR
i.v.
(maximum: 2 .0 mg/SD)
1.5 mg/m2/d =
.
mg
DNR
p.i. (1h)
30 mg/m2/d =
.
mg U
Date
L-ASP
p.i. (1h) 5,000 (E.coli- MEDAC/KYOWA)
U/m2/d =
Start Phase 2
Weight =
kg Height =
cm
BSA =
m2
33 1 8 15 22 29 36 43 50 57 64
CPM mg mg
p.i. (1h) 1,000 mg/m /d = (+ MESNA: 400 mg/m2 i.v. x3 at 0, 4, 8h)
ARA-C
i.v.
75 mg/m2/d =
6-MP
p.o. (28 d)
60 mg/m2/d =
.
mg mg
BM
Date of Start:
Date of End:
MTX
I.T.
( )*
Day 1 8 15 22
( )*
29 33 36 43 50
yes no 5% blasts in BM 30% of initial size Signature
Send copy on completion to national study coordinator Blasts in CSF Mediastinal tumor
Dose age-adapted: <1 MTX IT (mg) 6
1 8
2 10
3Y 12
* if CNS-2 or CNS-3 status, or traumatic LP: additional MTX IT on d 18/27
57
64 Day 33: Remission?
Dose modification? Cytostatic agents added or omitted? Description of modification(s) & reason(s):
YES NO
Fill in additional toxicity forms for Phase 1 & 2 !
ALL IC-BFM 2002
Appendix 3.0.b 1/1
Protocol I/Phase 1
Name: DOB: Day 1: LP ( _________ ) Weight: d/m/y kg Height: cm BSA: m2 Start: ___/___/___ End: ___/___ /___
mg Methotrexate IT at age-adjusted dosage (see below)
Day 8: mg Vincristine (1.5 mg/m2/d) i.v. (max. 2.0 mg/SD) ( ) mg Daunorubicin (30 mg/m2/d) p.i. over 1h in 50 ml NaCl 0.9% Diagnostics (obligatory): CBC+Diff+ABC, liver & spleen size. (optional): BMP Day 12: ( LP Day 15: ( ) U L-Asparaginase (E. coli, native, Fa. Medac) (5,000 U/m2/d) p.i. over 1h in 50 ml NaCl 0.9% mg Methotrexate IT at age-adjusted dosage (see below)
mg Vincristine (1.5 mg/m2/d) i.v. (max. 2.0 mg/SD) ) mg Daunorubicin (30 mg/m2/d) p.i. over 1h in 50 ml NaCl 0.9% U L-Asparaginase (E. coli, native, Fa. Medac) (5,000 U/m2/d) p.i. over 1h in 50 ml NaCl 0.9% Diagnostics (obligatory): BMP, CBC+Diff+ABC Day 18: U L-Asparaginase (E. coli, native, Fa. Medac) (5,000 U/m2/d) p.i. over 1h ( ) in 50 ml NaCl 0.9% LP ( if CNS 2 or CNS 3 status or traumatic LP ) mg Methotrexate IT at age-adjusted dosage (see below) Day 21: ( Day 22: ( Day 24: ( ) ) ) U L-Asparaginase (E. coli, native, Fa. Medac) (5,000 U/m2/d) p.i. over 1h in 50 ml NaCl 0.9% mg Vincristine (1.5 mg/m2/d) i.v. (max. 2.0 mg/SD) mg Daunorubicin (30 mg/m2/d) p.i. over 1h in 50 ml NaCl 0.9% U L-Asparaginase (E. coli, native, Fa. Medac) (5,000 U/m2/d) p.i. over 1h in 50 ml NaCl 0.9%
Day 27: U L-Asparaginase (E. coli, native, Fa. Medac) (5,000 U/m2/d) p.i. over 1h ( ) in 50 ml NaCl 0.9% LP ( if CNS 2 or CNS 3 status or traumatic LP ) mg Methotrexate IT at age-adjusted dosage (see below) Day 29: ( Day 30: ( ) ) mg Vincristine (1.5 mg/m2/d) i.v. (max. 2.0 mg/SD) mg Daunorubicin (30 mg/m2/d) p.i. over 1h in 50 ml NaCl 0.9% U L-Asparaginase (E. coli, native, Fa. Medac) (5,000 U/m2/d) p.i. over 1h in 50 ml NaCl 0.9%
Day 33: U L-Asparaginase (E. coli, native, Fa. Medac) (5,000 U/m2/d) p.i. over 1h ( ) in 50 ml NaCl 0.9% LP mg Methotrexate IT at age-adjusted dosage (see below) Diagnostics (obligatory): BMP, CBC+Diff+ABC Day 1 28: ( Prednisone taper: Day 29-31: ( Day 32-34: ( Day 35-37: ( <1 6 mg Prednisone (60 mg/m2/d) p.o./i.v. (Cave: hyperleukocytosis & risk of ) tumor lysis syndrome cautious dosage over first few days; see text) mg mg mg p.o. ): ): ): 1 8 mg mg mg 2 10 3 12 mg mg mg Age (yr) mg Methotrexate IT mg p.o. mg p.o. mg p.o.
Dosage of Methotrexate IT: Date:_____________ Signature:
Physician 1___________________Physician 2 ___________________
ALL IC-BFM 2002
Appendix 3.0.b 2
Start Phase 1 Center:
Weight =
kg Height =
cm
ALL IC-BFM 2002 : Protocol I'

Risk group: SR BCP - ALL
Date of Start: Date of End:
BSA =
m2
PRED mg
DOB:
p.o.
60 mg/m2/d =
Name:
VCR
i.v.
(maximum: 2 .0 mg/SD)
1.5 mg/m2/d =
.
mg
DNR
p.i. (1h)
30 mg/m2/d =
.
mg U
Date
L-ASP
U/m2/d =
Start Phase 2
Weight =
kg Height =
cm
BSA =
m2
33 1 8 15 22 29 36 43 50 57 64
CPM mg mg
p.i. (1h) 1,000 mg/m /d = 2 (+ MESNA: 400 mg/m i.v. x3 at 0, 4, 8h)
ARA-C
i.v.
75 mg/m2/d =
6-MP
p.o. (28 d)
60 mg/m2/d =
.
mg mg
3Y 12
Date of Start:
Date of End:
MTX
BM
I.T.
( )*
Day 1 8 15 22
( )*
29 33 36 43 50
yes no 5% blasts in BM 30% of initial size Signature
Send copy on completion to national study coordinator Blasts in CSF Mediastinal tumor
Dose age -adapted: <1 MTX IT (mg) 6
1 8
2 10
* if CNS-2 or CNS-3 status, or traumatic LP: additional MTX IT on day 18/27
57
64 Day 33: Remission ?
Dose modification? Cytostatic agents added or omitted? Description of modification(s) and reason(s):
YES NO
ALL IC-BFM 2002
Appendix 3.0.b 2/1
Protocol I'/Phase 1
Name: DOB: Day 1: LP ( _________ ) Weight: d/m/y kg Height: cm BSA: m2 Start: ___/___/___ End: ___/___ /___
mg Methotrexate IT at age-adjusted dosage (see below)
Day 8: mg Vincristine (1.5 mg/m2/d) i.v. (max. 2.0 mg/SD) ( ) mg Daunorubicin (30 mg/m2/d) p.i. over 1h in 50 ml NaCl 0.9% Diagnostics (obligatory): CBC+Diff+ABC, liver & spleen size. (optional): BMP Day 12: ( LP Day 15: ( ) U L-Asparaginase (E. coli, native, Fa. Medac) (5,000 U/m2/d) p.i. over 1h in 50 ml NaCl 0.9 % mg Methotrexate IT at age-adjusted dosage (see below) mg Vincristine (1.5 mg/m2/d) i.v. (max. 2.0 mg/SD)
mg Daunorubicin (30 mg/m2/d) p.i. over 1h in 50 ml NaCl 0.9 % U L-Asparaginase (E. coli, native, Fa. Medac) (5,000 U/m2/d) p.i. over 1h in 50 ml NaCl 0.9 % Diagnostics (obligatory): BMP, CBC+Diff+ABC ) Day 18: U L-Asparaginase (E. coli, native, Fa. Medac) (5,000 U/m2/d) p.i. over 1h ( ) in 50 ml NaCl 0.9 % LP ( if CNS 2 or CNS 3 status or traumatic LP ) mg Methotrexate IT at age-adjusted dosage (see below) Day 21: ( Day 22: ( Day 24: ( ) ) ) U L-Asparaginase (E. coli, native, Fa. Medac) (5,000 U/m2/d) p.i. over 1h in 50 ml NaCl 0.9 % U L-Asparaginase (E. coli, native, Fa. Medac) (5,000 U/m2/d) p.i. over 1h in 50 ml NaCl 0.9 % mg Vincristine (1.5 mg/m2/d) i.v. (max. 2.0 mg/SD)
Day 27: U L-Asparaginase (E. coli, native, Fa. Medac) (5,000 U/m2/d) p.i. over 1h ( ) in 50 ml NaCl 0.9 % LP ( if CNS 2 or CNS 3 status or traumatic LP ) mg Methotrexate IT at age-adjusted dosage (see below) Day 29: ( Day 30: ( mg Vincristine (1.5 mg/m2/d) i.v. (max. 2.0 mg/SD) ) ) U L-Asparaginase (E. coli, native, Fa. Medac) (5,000 U/m2/d) p.i. over 1h in 50 ml NaCl 0.9 %
Day 33: L-Asparaginase (Fa. Medac) (5,000 U/m2/d) p.i. over 1h ( ) in 50 ml NaCl 0.9 % LP mg Methotrexate IT at age-adjusted dosage (see below) Diagnostics (obligatory): BMP, CBC+Diff+ABC Day 1 28: ( Prednisone taper: Day 29-31: ( Day 32-34: ( Day 35-37: ( <1 6 mg Prednisone (60 mg/m2/d) p.o./i.v. (Cave: hyperleukocytosis & risk of ) tumor lysis syndrome cautious dosage over first few days; see text) mg mg mg p.o. ): ): ): 1 8 mg mg mg 2 10 3 12 mg mg mg Age (yr) mg Methotrexate IT mg p.o. mg p.o. mg p.o.
Dosage of Methotrexate IT: Date:_____________ Signature:
ALL IC-BFM 2002
Appendix 3.0.b 1/2+2/2
Protocol I/I'/Phase 2
Name: DOB: Weight: d/m/y kg Height: cm BSA: m2 Start: ___/___/___ End: ___/___ /___
Lab tests: CBC, electrolytes, creatinine, urea, G, U/S-osmolality, alb, ALT, AST, bilirubin, urinalysis Day 36: ( ) mg Cyclophosphamide (1,000 mg/m2/d) p.i. over 1h in 50 ml NaCl 0.9% mg Mesna (400 mg/m2/SD) i.v. at 0, 4 & 8 h ml i.v. crystalloids (3,000 ml/m2/24h: 5% G / 0.45% NaCl aa + 90 mmol/m2/24h 7.45% KCl) p.i. for 24 h from end of CPM infusion I > O + 400 ml/m2/12h 0.5 mg/kg (max. 20 mg) furosemide i.v. ____________ ml/m2/12h ____________ mg i.v. mg Cytarabine (75 mg/m2/d) i.v. )LP ) BMP (in case of NR day 33) ) mg Cytarabine (75 mg/m2/d) i.v. ) mg Methotrexate IT at age-adjusted dosage (see below) mg Cytarabine (75 mg/m2/d) i.v. ) mg Cyclophosphamide (1,000 mg/m2/d) p.i. over 1h in 50 ml NaCl 0.9% mg Mesna (400 mg/m2/SD) i.v. at 0, 4 & 8 h ml i.v. crystalloids (3,000 ml/m2/24h: 5% G / 0.45% NaCl aa + 90 mmol/m2/24h 7.45% KCl) p.i. for 24 h from end of CPM infusion I > O + 400 ml/m2/12h 0.5 mg/kg (max. 20 mg) furosemide i.v. ____________ ml/m2/12h ____________ mg i.v. ____________ ml/m2/12h ____________ mg i.v. ) mg Methotrexate IT at age-adjusted dosage (see below) mg Cytarabine (75 mg/m2/d) i.v. ____________ ml/m2/12h ____________ mg i.v.
Fluid balance: + fluid balance: Furosemide: Day 38 41: ( Day 45: (
Day 45 48: ( Day 52: (
Day 52 55: ( Day 59: ( )LP
Day 59 62: ( Day 64: (
Lab tests: CBC, electrolytes, creatinine, urea, G, U/S-osmolality, alb, ALT, AST, bilirubin, urinalysis )
Fluid balance: + fluid balance: Furosemide: Day 36 63: ( )
mg 6-Mercaptopurine (60 mg/m2/d) p.o.
Dosage of Methotrexate IT:
<1 6
1 8
2 10
3 12
Age (yr) mg Methotrexate IT
Date:_____________ Signature:
ALL IC-BFM 2002
Appendix 3.0.c 1
Weight =
kg
ALL IC-BFM 2002 : Protocol mM

Center:
Height =
cm
Risk group:
Name: DOB:
SR BCP ALL
IR BCP ALL
BSA
6-MP = mg/d mg/SD .
p.o. (56 d)
25 mg/m2/d
(in evening, on empty stomach, w/o milk)
MTX
p.i. (24h)
2,000 mg/m2 =
(10% in 0.5 h, 90% in 23.5 h)
LCV-Rescue 15 mg/m2 i.v. at h: 42, 48, 54 mg

BM
MTX
I.T. (1h after start of MTX inf.)
Dose age -adapted:
<1y: 6 mg;
1y: 8 mg;
2y: 10 mg;
>=3y: 12 mg
Day 1
Date
15
22
29
36
43
50
56
Dose modification? Cytostatic agents added or omitted? YES NO Description of modification(s) & reason(s):
Fill in additional toxicity form per each MD MTX !
Signature
Send copy on completion to national study coordinator
ALL IC-BFM 2002
Appendix 3.0.c 1.1
Protocol mM
SR BCP-ALL 1. MTX Name: DOB: Weight: d/m/y 2. MTX kg IR BCP-ALL 3.MTX Height: CLcr: 4. MTX cm ml/min/m2 BSA: m2 Start: ___/___/___ d/m/y
Prior to each MD MTX Lab tests: CBC, electrolytes, G, creatinine, urea, U/S-osmolality, albumin, ALT, AST, ALP, bilirubin, urinalysis Day 1 pre MTX hydration: ml NaHCO3 (2 mmol/kg) + ml aqua pro inj. (2 ml/kg) p.i. (1 h) Thereafter: 500 ml (NaCl 0.45% / G 5% aa) + 40 mmol NaHCO3 + 10 ml KCl 7.45% Day 1 (1400) urine pH 7 mg Methotrexate (2,000 mg/m2/d) p.i. (24 h) mg Methotrexate (1/10) loading dose p.i. (30 min) mg Methotrexate (9/10) + + ml G 5% / NaCl 0.45% aa mmol NaHCO3 ml KCl 7.45% p.i. (23.5 h) (3,000 ml/m2/24h) (180 mmol/m2/24h) (90 ml/m2/24h) ml/h
Day 1 (1500) Day 2 + 3 +
LP:
mg MTX IT post - MTX hydration:
Dosage:
<1 6
1 8
2 10
3 12
Age (yr) mg MTX IT
+ + Day 2 + 3 +
ml G 5% / NaCl 0.45% aa mmol NaHCO3 ml KCl 7.45% Leucovorin rescue:
(3,000 ml/m2/24h) (180 mmol/ m2/24h) (90 ml/m2/24h)
mg LCV (15 mg/m2/SD) i.v. at: _______42 h, _______48 h, _______54 h Day 1 3 Day 1 3 mg 6-Mercaptopurine (25 mg/m2/d) p.o. in evening on empty stomach w/o milk Monitoring of U-pH (every portion with dipstick) If U-pH < 7 20 mmol NaHCO3 / 20 ml aqua pro inj. p.i. over 30 min _______ of extra alkali infusions Fluid balance: If I > O + 400 ml/m2/12h 0.5 mg/kg (max. 20 mg) furosemide i.v. + fluid balance: Furosemide: _____ _____ _____ _____ _____ _____ _____ _____ _____ ml/m2/12h _____ mg i.v.
Supportive: Drug Date 1. _____________________ 2. _____________________ 3. _____________________ 4. _____________________ Date:________ Signature: Physician 1_______________ Physician 2 _______________
ALL IC-BFM 2002
Appendix 3.0.c 2
Center:
Weight =
kg
ALL IC-BFM 2002 :Protocol M

SR T ALL IR T ALL
Name: DOB:
Height =
cm
Risk group:
BSA
6-MP = mg/d mg/SD .
p.o. (56 d)
(in evening, on empty stomach, w/o milk)
25 mg/m2/d
MTX
p.i. (24h)
5,000 mg/m2 =
(10% in 0.5 h, 90% in 23.5 h)
LCV-Rescue 15 mg/m2 i.v. at h: 42, 48, 54 mg

BM
MTX
I.T. (1h after start of MTX inf.)
Dose age -adapted:
<1y: 6 mg;
1y: 8 mg;
2y: 10 mg;
>=3y: 12 mg
Day 1
MTX (mol/l)
24 h 36 h 42 h 48 h 54 h
Date
8
2.MTX
15
CF - Rescue (mg)
22
24 h 36 h 42 h 48 h 54 h
29
3.MTX
MTX (mol/l)
36
43
CF - Rescue (mg)
50
24 h 36 h 42 h 48 h 54 h
56
4.MTX
MTX (mol/l) CF - Rescue (mg)
1.MTX
MTX (mol/l) CF - Rescue (mg)
24 h
Dose modification? Cytostatic agents added or omitted? YES NO Description of modification(s)/reason(s):
36 h
42 h
48 h
54 h
Extended Rescue Yes until hour No
Extended Rescue Yes until hour Send copy on completion to national study coordinator No
Signature
Fill in additional toxicity form for each HD MTX !
ALL IC-BFM 2002
Appendix 3.0.c 2.1
Protocol M
1. MTX Name: DOB: Weight: d/m/y 2. MTX kg 3.MTX Height: CLcr: 4. MTX cm BSA: m2 2 ml/min/m Start: ___/___/___ d/m/y
Prior to each HD MTX Lab tests: CBC, MTX level, electrolytes, G, creatinine, urea, U/S-osmolality, alb, ALT, AST, ALP, bilirubin, urinalysis, (baseline MTX level in all but first HD MTX) Day 1 pre MTX hydration: ml NaHCO3 (2 mmol/kg) + ml aqua pro inj. (2 ml/kg) p.i. (1 h) Thereafter: 500 ml (NaCl 0.45% / G 5% aa) + 40 mmol NaHCO3 + 10 ml KCl 7.45% Day 1 (1400) urine pH 7 mg Methotrexate (5,000 mg/m2/d) p.i. (24 h) mg Methotrexate (1/10) loading dose p.i. (30 min) mg Methotrexate (9/10) + + ml G 5% / NaCl 0.45% aa mmol NaHCO3 ml KCl 7.45% p.i. (23.5 h) (3,000 ml/m2/24h) (180 mmol/m2/24h) (90 ml/m2/24h) ml/h
Day 1 (1500) Day 2 + 3 +
LP:
mg MTX IT post - MTX hydration:
Dosage:
<1 6
1 8
2 10
3 12
Age (yr) mg MTX IT
+ + Day 2 + 3 +
ml G 5% / NaCl 0.45% aa mmol NaHCO3 ml KCl 7.45% Leucovorin rescue:
(3,000 ml/m2/24h) (180 mmol/ m2/24h) (90 ml/m2/24h)
mg LCV (15 mg/m2/SD) i.v. at: _______42 h, _______48 h, _______54 h See also text [section 2.2.3.2 (p 58); section 3.10 (p 135)] & Appendix 3.1 [Leucovorin Rescue Plan]. Day 1 3 Day 1 3 mg 6-Mercaptopurine (25 mg/m2/d) p.o. in evening on empty stomach w/o milk Monitoring of U-pH (every portion with dipstick) If U-pH < 7 20 mmol NaHCO3 / 20 ml aqua pro inj. p.i. over 30 min _______ of extra alkali infusions Fluid balance: If I > O + 400 ml/m2/12h 0.5 mg/kg (max. 20 mg) furosemide i.v. + fluid balance: Furosemide: _____ _____ _____ _____ _____ _____ _____ _____ _____ ml/m2/12h _____ mg i.v.
Supportive: Drug Date 1. _____________________ 2. _____________________ 3. _____________________ 4. _____________________ Date:________ Signature: Physician 1_______________ Physician 2 _______________
ALL IC-BFM 2002
Appendix 3.0.d
Start Phase 1
ALL IC-BFM 2002 : Protocol II

SR -1 HR-2A IR-1 1.
Center:
Weight =
kg Height =
cm
Therapy arm:
BSA =
m2
HR-2A 2.
HR-2B
DEXA mg
Name: DOB:
p.o./i.v.
10 mg/m2/d = mg mg U
Date
VCR
i.v.
(maximum: 2.0 mg/SD)
1.5 mg/m2/d =
DOX
p.i. (1h)
30 mg/m2/d =
L-ASP p.i. (1h) 10,000 U/m2/d =
(E.coli- MEDAC/KYOWA)
Start Phase 2
Weight =
kg Height =
cm
BSA =
m2
15
22
29
36
43
49
CPM mg mg
p.i. (1h) 1,000 mg/m /d = 2 (+MESNA: 400 mg/m i.v. x3 at 0, 4, 8h)
6-TG p.o. (14 d) 60 mg/m2/d =
.
mg
MTX BM Day 1
YES NO
I.T.
mg
( )*
( )*
Dose age-adapted: <1 MTX IT (mg) 6
1 8
2 10
3Y 12
Cranial radiotherapy:
No
* If CNS-positive: additional MTX IT on day 1 & 18
15
22
29
36
43
49
Dose modification? Cytostatic agents added or omitted? Description of modification(s) and reason(s):
Yes, from till Total dose: Fractions (n):

Signature
Start of 6- MP/MTX:
ARA-C
i.v.
75 mg/m2/d =
Gy
ALL IC-BFM 2002
Appendix 3.0.d 1
Protocol II/Phase 1
SR-1 IR-1 HR-2A 1. 2. HR-2B
Name: DOB: Day 1: ( ) Diagnostics: LP ( if CNS 3 status )
Weight: d/m/y
kg Height: cm BSA: m2 Start: ___/___/___ End: ___/___ /___
BMP (optional) mg Methotrexate IT at age-adjusted dosage (see below)
Day 8: (
mg Vincristine (1.5 mg/m2/d) i.v. (max. 2.0 mg/SD) mg Doxorubicin (30 mg/m2/d) p.i. over 1h in 50 ml NaCl 0.9% U L-Asparaginase (E. coli, native, Fa. Medac) (10,000 U/m2/d) p.i. over 1h in 50 ml NaCl 0.9% U L-Asparaginase (E. coli, native, Fa. Medac) (10,000 U/m2/d) p.i. over 1h in 50 ml NaCl 0.9% mg Vincristine (1.5 mg/m2/d) i.v. (max. 2.0 mg/SD) mg Doxorubicin (30 mg/m2/d) p.i. over 1h in 50 ml NaCl 0.9% U L-Asparaginase (E. coli, native, Fa. Medac) (10,000 U/m2/d) p.i. over 1h in 50 ml NaCl 0.9% U L-Asparaginase (E. coli, native, Fa. Medac) (10,000 U/m2/d) p.i. over 1h in 50 ml NaCl 0.9% mg Methotrexate IT at age-adjusted dosage (see below)
Day 11: ( Day 15: (
) )
Day 18: ( ) LP ( if CNS 3 status ) Day 22: ( Day 29: (
) ) )
mg Vincristine (1.5 mg/m2/d) i.v. (max. 2.0 mg/SD) mg Doxorubicin (30 mg/m2/d) p.i. over 1h in 50 ml NaCl 0.9% mg Vincristine (1.5 mg/m2/d) i.v. (max. 2.0 mg/SD) mg Doxorubicin (30 mg/m2/d) p.i. over 1h in 50 ml NaCl 0.9% mg Dexamethasone (10 mg/m2/d) p.o./i.v. mg mg mg mg mg 1 8 2 10 3 12 mg mg mg Age (yr) mg Methotrexate IT mg p.o./i.v. mg p.o./i.v. mg p.o./i.v. mg p.o./i.v.
Day 1 21: ( Dexamethasone taper: Day 22-24: ( Day 25-27: ( Day 28-30: ( -
): ): ): <1 6
Dosage of Methotrexate IT: Cave: Supportive therapy: Date:_____________ Signature:
Allergic reactions to L-ASP are frequent at this stage of treatment. See text for alternative therapy. See text for SDD, PCP prophylaxis, prevention/therapy of ulcer disease, etc.
ALL IC-BFM 2002
Appendix 3.0.d 2
Protocol II/Phase 2
SR-1 IR-1 HR-2A 1. 2. HR-2B
Name: DOB:
Weight: d/m/y
Lab tests: CBC, electrolytes, creatinine, urea, G, U/S-osmolality, alb, ALT, AST, bilirubin, urinalysis Day 36: ( ) mg Cyclophosphamide (1,000 mg/m2/d) p.i. over 1h in 50 ml NaCl 0.9% mg Mesna (400 mg/m2/SD) i.v. at 0, 4 & 8 h ml i.v. crystalloids (3,000 ml/m2/24h: 5% G / 0.45% NaCl aa + 90 mmol/m2/24h 7.45% KCl) p.i. for 24 h from end of CPM infusion I > O + 400 ml/m2/12h 0.5 mg/kg (max. 20 mg) furosemide i.v. ____________ ml/m2/12h ____________ mg i.v. ____________ ml/m2/12h ____________ mg i.v.
Fluid balance: + fluid balance: Furosemide: Day 38: (
)LP
mg Methotrexate IT at age-adjusted dosage (see below) mg Cytarabine (75 mg/m2/d) i.v. ) mg Methotrexate IT at age-adjusted dosage (see below) mg Cytarabine (75 mg/m2/d) i.v. ) mg 6-Thioguanine (60 mg/m2/d) p.o. ) <1 6 1 8 2 10 3 12 Age (yr) mg Methotrexate IT
Day 38 41: ( Day 45: ( )LP
Day 45 48: ( Day 36 49: ( -
Dosage of Methotrexate IT: Supportive therapy: Date:_____________ Signature:
See text for SDD, PCP prophylaxis, prevention/therapy of ulcer disease, etc.
ALL IC-BFM 2002
Appendix 3.0.e
Start Phase 1
ALL IC-BFM 2002:Protocol III

SR -2 IR-2 1. IR-2/HR-1
Center:
Weight =
kg Height =
cm
BSA =
m2
Therapy arm 1. 2. SR-2
HR-1 2. 3.
DEXA mg
Name: DOB:
p.o./i.v.
10 mg/m2/d = mg
VCR
i.v.
1.5 mg/m2/d =
. .
mg U
Date
DOX
p.i. (1h)
30 mg/m2/d =
L-ASP p.i. (1h) 10,000 U/m2/d =
Start Phase 2
Weight =
kg Height =
cm
BSA =
m2
1 mg mg
15
22
29
CPM
p.i. (1h) 500 mg/m /d = 2 (+MESNA: 200 mg/m i.v. x3 at 0, 4, 8h)
6-TG p.o. (14 d) 60 mg/m2/d =
.
mg ( )* BM mg
MTX
I.T.
Dose age -adapted: <1 MTXIT (mg) 6
1 8
2 10
3Y 12
Cranial radiotherapy:
No
* If CNS positive: additional MTX IT on day 1
Day
1
8
YES NO
15
22
29
Yes, from till Total dose: Fractions (n):

Signature
Start of 6 - MP/MTX:
ARA- C
i.v.
75 mg/m2/d =
Gy
ALL IC-BFM 2002
Appendix 3.0.e 1
Protocol III/Phase 1
SR-2 1. 2. IR-2/HR-1 1. 2. 3.
Name: DOB: Day 1: ( Diagnostics: LP ( if CNS 3 status ) )
Weight: d/m/y
mg Vincristine (1.5 mg/m2/d) i.v. (max. 2.0 mg/SD) mg Doxorubicin (30 mg/m2/d) p.i. over 1h in 50 ml NaCl 0.9% U L-Asparaginase (E. coli, native, Fa. Medac) (10,000 U/m2/d) p.i. over 1h in 50 ml NaCl 0.9% BMP (optional) mg Methotrexate IT at age-adjusted dosage (see below)
Day 4: ( Day 8: (
) )
U L-Asparaginase (E. coli, native, Fa. Medac) (10,000 U/m2/d) p.i. over 1h in 50 ml NaCl 0.9% mg Vincristine (1.5 mg/m2/d) i.v. (max. 2.0 mg/SD) mg Doxorubicin (30 mg/m2/d) p.i. over 1h in 50 ml NaCl 0.9% U L-Asparaginase (E. coli, native, Fa. Medac) (10,000 U/m2/d) p.i. over 1h in 50 ml NaCl 0.9% U L-Asparaginase (E. coli, native, Fa. Medac) (10,000 U/m2/d) p.i. over 1h in 50 ml NaCl 0.9% mg Dexamethasone (10 mg/m2/d) p.o./i.v. ) mg mg mg mg mg 1 8 2 10 3 12 mg mg mg Age (yr) mg Methotrexate IT mg p.o./i.v. mg p.o./i.v mg p.o./i.v. mg p.o./i.v. ): ): ): <1 6
Day 11: (
Day 1 14: ( Dexamethasone taper: Day 15-17: ( Day 18-20: ( Day 21-23: ( -
Dosage of Methotrexate IT: Cave: Supportive therapy: Date:_____________ Signature:
Allergic reactions to L-ASP are frequent at this stage of treatment. See text for alternative therapy. See text for SDD, PCP prophylaxis, prevention/therapy of ulcer disease, etc.
ALL IC-BFM 2002
Appendix 3.0.e 2
Protocol III/Phase 2
SR-2 1. 2. IR-2/HR-1 1. 2. 3.
Name: DOB:
Weight: d/m/y
Lab tests: CBC, electrolytes, creatinine, urea, G, U/S-osmolality, alb, ALT, AST, bilirubin, urinalysis Day 15: ( ) mg Cyclophosphamide (500 mg/m2/d) p.i. over 1h in 50 ml NaCl 0.9% mg Mesna (200 mg/m2/SD) i.v. at 0, 4 and 8 h ml i.v. crystalloids (1,500 ml/m2/12h: 5% G / 0.45% NaCl aa + 45 mmol/m2/12h 7.45% KCl) p.i. for 12 h from end of CPM infusion I > O + 400 ml/m2/12h 0.5 mg/kg (max. 20 mg) furosemide i.v. ____________ ml/m2/12h ____________ mg i.v.
Fluid balance: + fluid balance: Furosemide: Day 17: (
)LP
mg Methotrexate IT at age-adjusted dosage (see below) mg Cytarabine (75 mg/m2/d) i.v. ) mg Methotrexate IT at age-adjusted dosage (see below) mg Cytarabine (75 mg/m2/d) i.v. ) mg 6-Thioguanine (60 mg/m2/d) p.o. ) <1 6 1 8 2 10 3 12 Age (yr) mg Methotrexate IT
Day 17 20: ( Day 24: ( )LP
Day 24 27: ( Day 15 28: ( -
Dosage of Methotrexate IT:
Supportive therapy: Date:_____________ Signature:
See text for SDD, PCP prophylaxis, prevention/therapy of ulcer disease, etc.
ALL IC-BFM 2002 Center:
Appendix 3.0.f
Weight =
kg
ALL IC-BFM 2002 :Block HR-1

1.
Name: DOB:
Height =
cm
BSA
Therapy arm:
2. HR - 1' block HR - 2A HR - 1
HR - 2B
DEXA p.o ./i.v. 20 mg/m2 /d = = VCR i.v.

(maximum : 2.0 mg/SD)
. .
mg/d mg/SD mg/SD
1.5 mg/m 2/d
HD ARA -C p.i. (3h) 2,000 mg/m 2 x2 =

(q 12 h)
HD MTX p.i. (24h) 5,000 mg/m 2 CF-Rescue i.v. 15 mg/m 2 x3 (h: 42,48,54)
(+MESNA 70 mg/m2 i.v. x3 at 0, 4, 8h)
= = mg/SD
mg
CPM p.i. (1h) 200 mg/m2 x5 (q 12h) = L-ASP p.i. (2h) 25,000 U/m 2/d = = / /
mg/SD U mg
(E.coli- MEDAC /KYOWA)
BM
MTX/ARA - C/PRED I.T.
Day 4 5 6 11
12 10 8 6
30 26 20 16
10 mg 8 mg 6 mg 4 mg
dose by age => 3 Y => 2 < 3 Y => 1 < 2 Y <1Y
1h after start HD - MTX
Date MTX (mol/l)

24 h
Data before start of block: No
Fill in additional toxicity form ! CF- Rescue (mg) Extended Rescue
Patient in remission ?
Yes
36 h 42 h 48 h 54 h
Yes until hour
No
Signature
ALL IC-BFM 2002
Appendix 3.0.f 1
BLOCK HR 1'
Name: DOB: Weight: d/m/y kg CLcr: Height: ml/min/m2 cm BSA: Start: m2 / / d/m/y
Lab tests prior to start: CBC, electrolytes, creatinine, urea, U/S-osmolality, G, alb, ALT, AST, ALP, bilirubin, urinalysis; in addition TC O2 Lab tests on day 2 + 3: electrolytes, creatinine, urea, G, ALT, AST, ALP, bilirubin Day 1 5 Day 1 mg Dexamethasone p.o./i.v. (20 mg/m2/d): pre MTX hydration: ml NaHCO3 (2 mmol/kg) + ml aqua pro inj. (2 ml/kg) p.i. (1 h) Thereafter: 500 ml (NaCl 0.45% / G 5% aa) + 40 mmol NaHCO3 + 10 ml KCl 7.45% Day 1 + Day 1 (1400) urine pH 7 mg Methotrexate (1/10) loading dose p.i. (30 min) mg Methotrexate (9/10) + + Day 1 (1500) Day 1 3 LP: ml G 5% / NaCl 0.45% aa mmol NaHCO3 ml KCl 7.45% mg MTX IT, p.i. (23.5 h) (3,000 ml/m2/24) (180 mmol/m2/24h) (90 ml/m2/24h) ml/h mg Vincristine (1.5 mg/m2/d) slowly i.v. (max. 2.0 mg/SD), at least 1h before MTX mg Methotrexate (5,000 mg/m2/d) p.i. (24 h) mg, mg, mg
mg ARA-C IT,
mg Prednisone IT
Monitoring of U-pH (every portion with dipstick) If U-pH < 7 20 mmol NaHCO3 / 20 ml aqua pro inj. p.i. over 30 min _______ of extra alkali infusions post - MTX hydration: + + ml G 5% / NaCl 0.45% aa mmol NaHCO3 ml KCl 7.45% Leucovorin rescue: (3,000 ml/m2/24h) (180 mmol/ m2/24h) (90 ml/m2/24h)
Day 2 + 3
Day 2 + 3
mg LCV (15 mg/m2/SD) i.v. at: _______42 h, _______48 h, _______54 h See also text [section 2.2.3.2 (p 58); section 3.10 (p 135)] & Appendix 3.1 [Leucovorin Rescue Plan] Day 2 4 mg Cyclophosphamide (200 mg/m2/SD) p.i. (1 h) 5 doses q 12 h: 1. dose on day 2 (2100), 5. dose on day 4 (2100) mg Mesna (70 mg/m2/SD) i.v. at 0, 4 & 8 h from start of each CPM infusion INFUSION ml G 5% / NaCl 0.45% aa (3,000 ml/m2/24h) + ml KCl 7.45% Day 5 900 + 2100 Day 5 8 Day 6 Day 6 Day 11 Day 11 + Date: Signature: (90 ml/m2/24h)
Day 4 - 6
+ +
mg Cytarabine (2,000 mg/m2/SD) in 250 ml G 5%, p.i. (3 h) 2 doses 12 h apart (900 + 2100); close monitoring; Cave: ataxia, nystagmus Dexamethasone eye drops: tid; B6: 150 mg/m2 i.v./p.o. q 12h for 2 3 days mg Vincristine (1.5 mg/m2/d) slowly i.v. (max. 2.0 mg/SD), 10 12h before L-ASP ___________ U E. coli L-asparaginase (25,000 U/m2/d) in 250 ml NaCl 0.9%, p.i. (2 h) ___________ U E. coli L-asparaginase (25,000 U/m2/d) in 250 ml NaCl 0.9%, p.i. (2 h) g G-CSF (5 g/kg/d s.c.) until ANC > 5,000/L mg furosemide i.v. (0.5 mg/kg/SD, max. 20 mg) Supportive therapy: HT3 blocker & other indispensable medications pro re nata Physician 2
Fluid balance: q 12h, if I > O + 400 ml/m2 /12h Physician 1
ALL IC-BFM 2002
Appendix 3.0.g
Center:
Weight =
kg
ALL IC-BFM 2002 : Block HR-2

1.
Name: DOB:
Height =
cm
Therapy arm:
2. HR - 2' block HR - 2A HR - 1
HR - 2B
BSA
DEXA p.o. /i.v. VDS i.v.

20 mg/m 2/d =
. . .
mg/d mg/SD mg/SD
3 mg/m 2/d = 30 mg/m2 =
DNR p.i. (24h)
HD MTX p.i. (24h) 5,000 mg/m 2 = CF-Rescue i.v. x3 (h: 42,48,54) IFO p.i. (1h) L- ASP p.i. (2h)
2
mg = mg/SD mg/SD
15 mg/m2
800 mg/m 2 x5 = 25,000 U/m 2/d = = / /
(+ MESNA: 300 mg/m i.v. x3 at 0, 4, 8h)
U mg
BM
* 4 5 6 11
MTX/ARA- C/PRED I.T.
Day
Date
MTX (mol/l)
12 10 8 6
30 26 20 16
10 mg 8 mg 6 mg 4 mg
dose by age => 3 Y => 2 < 3 Y => 1 < 2 Y <1Y * Only in CNS-positive pts
1h after start HD MTX
Data before start of block: No
Fill in additional toxicity form !

CF- Rescue (mg)
Patient in remission?
Yes
24 h 36 h 42 h 48 h 54 h

Signature
ALL IC-BFM 2002
Appendix 3.0.g 1
BLOCK HR 2'
Name: DOB: Weight: d/m/y CLcr: kg Height: ml/min/m2 cm BSA: Start: m2 / / d/m/y
Lab tests prior to start: CBC, MTX level, electrolytes, creatinine, urea, U/S-osmolality, G, alb, ALT, AST, ALP, bilirubin, urinalysis; in addition TC O2 Lab tests on day 2 + 3: electrolytes, creatinine, urea, G, ALT, AST, ALP, bilirubin Day 1 5 Day 1 mg Dexamethasone p.o./i.v. (20 mg/m2/d): pre MTX hydration: ml NaHCO3 (2 mmol/kg) + ml aqua pro inj. (2ml/kg) p.i. (1 h) Thereafter 500 ml (NaCl 0.45% / G 5%) + 40 mmol NaHCO3 + 10 ml KCl 7.45% Day 1 Day 1 (1400) urine pH 7 + mg Vindesine (3 mg/m2/d) slowly i.v. (max. 5.0 mg/SD), at least 1 h before MTX mg Methotrexate (5,000 mg/m2/d) p.i. (24 h) mg Methotrexate (1/10) loading dose p.i. (30 min) mg Methotrexate (9/10) + + Day 1 (1500) +Day 5: CNS + LP: ml G 5% / NaCl 0.45% aa mmol NaHCO3 ml KCl 7.45% mg MTX IT, ditto p.i. (23.5 h) (3,000 ml/m2/24h) (180 mmol/m2/24h) (90 ml/m2/24h) ml/h mg, mg, mg
mg ARA-C IT, ditto
mg Prednisone IT ditto
Day 1 3 Monitoring of U-pH (every portion with dipstick) If U-pH < 7 20 mmol NaHCO3 / 20 ml aqua pro inj. p.i. over 30 min : _______ of extra alkali infusions mg furosemide i.v. (0.5 mg/kg/SD, max. 20 mg) Fluid balance: q 12h, if I > O + 400 ml/m2 /12h Day 2 + 3 + + + Day 2 + 3 Day 2 4 + post - MTX hydration: ml G 5% / NaCl 0,45% aa mmol NaHCO3 ml KCl 7.45% Leucovorin rescue: (3,000 ml/m2/24h) (180 mmol/ m2/24h) (90 ml/m2/24h) mg LCV (15 mg/m2/SD) i.v. at: __ 42 h, __ 48 h, __ 54 h
See also text [section 2.2.3.2 (p 58); section 3.10 (p 135)] & Appendix 3.1 [Leucovorin Rescue Plan] mg Ifosfamide (800 mg/m2/SD) p.i. (1 h) 5 doses q 12 h: 1. dose on day 2 (2100), 5. dose on day 4 (2100) mg Mesna (300 mg/m2/SD) i.v. at 0, 4 & 8 h from start of each IFO infusion INFUSION: ml G 5% / NaCl 0.45% aa (3,000 ml/m2/24h) + ml KCl 7.45% (90 ml/m2/24h) Fluid balance: q 12 h If I > O + 400 ml/m2 /12h mg furosemide i.v. (0.5 mg/kg/SD, max. 20 mg) mg Daunorubicin (30 mg/m2/SD) in + + ml NaCl 0.9%, p.i. (24 h)
Day 4 - 6 Day 1 - 6 Day 5 Day 6 Day 6 Day 11 Day 11 + Date: Signature:
mg Vindesine (3 mg/m2/d) slowly i.v. (max. 5.0 mg/SD), 10 12 h before L-ASP U E. coli L-asparaginase (25,000 U/m2/d) in 250 ml NaCl 0.9%, p.i. (2 h) U E. coli L-asparaginase (25,000 U/m2/d) in 250 ml NaCl 0.9%, p.i. (2 h) g G-CSF (5 g/kg/d s.c.) until ANC > 5,000/L Physician 1 Supportive therapy: HT3 blocker & other indispensable medications pro re nata Physician 2
ALL IC-BFM 2002
Appendix 3.0.h
Weight =
kg
ALL IC-BFM 2002 : Block HR-3

Center:
1.
Name: DOB:
Height =
cm
Therapy arm:
2. HR - 1
HR - 3' block HR - 2A
HR - 2B
BSA
DEXA
p.o./i.v.
20 mg/m2/d =
(q 12 h)
mg/d mg/SD mg/SD
HD ARA-C p.i. (3h) 2,000 mg/m2 x4 = VP-16

p.i. (1h)
100 mg/m2 x5 =
(q 12 h)
L-ASP
U/m2/d =
MTX/ARA-C/PRED
12 10 8 6 30 26 20 16 10 mg 8 mg 6 mg 4 mg
I.T.
=
dose by age
/
=> 3 Y => 2 < 3 Y => 1 < 2 Y <1Y
mg
Day
11
Date Fill in additional toxicity form ! No
Data before start of block:
Patient in remission?
Yes
YES NO
Signature
ALL IC-BFM 2002
Appendix 3.0.h 1
BLOCK HR 3'
Name: DOB: Weight: d/m/y CLcr: kg Height: ml/min/m2 cm BSA: Start: m2 / / d/m/y
Lab tests prior to start: CBC, electrolytes, creatinine, urea, U/S-osmolality, G, alb, ALT, AST, ALP, bilirubin, urinalysis; in addition TC O2 Lab tests on day 2 + 3: electrolytes, creatinine, urea, G, ALT, AST, ALP, bilirubin Day 1 5 Day 1 2 mg Dexamethasone p.o./i.v. (20 mg/m2/d): mg Cytarabine mg, mg, mg
Day 1 - 6
INFUSION
(2,000 mg/m2/SD) p.i. (3 h) 4 doses 12 h apart 1,000 mg in 50 ml G 5% Cave: ataxia, nystagmus Dexamethasone eye drops: tid Day 1 3 B6: 150 mg/m2 i.v./p.o. q 12 h Day 1 3 (3,000 ml/m2/24h) + (90 ml/m2/24h)
ml G 5% / NaCl 0.45% aa ml KCl 7.45% Day 3 5 -
mg Etoposide (100 mg/m2/SD) // Etopophos (113 mg/m2/SD) p.i. (1 h) in ml NaCl 0.9% (400 ml/m2) 5 doses 12 h apart 1. dose on day 3 at 2100 h; 5. dose on day 5 at 2100 h ECG monitor during & for 5 h after infusion Cave: dysrhythmia, hypotension, allergic reactions, anaphylaxis Be prepared with (methyl)prednisolone 5 mg/kg & clemastine (dosage by age: 0.25 2 mg slowly i.v. q 6 8 h) or promethazine (dosage by age: 0.25 1 mg/kg slowly i.v. q 8 h) for case of serious allergic event
Day 5 Day 6 Day 11 Day 11 + Day 1 - 6 + fluid balance: Furosemide: +
LP:
mg MTX IT,
mg ARA-C IT,
mg Prednisone IT
U E. coli L-asparaginase (25,000 U/m2/d) in 250 ml NaCl 0.9%, p.i. (2 h) U E. coli L-asparaginase (25,000 U/m2/d) in 250 ml NaCl 0.9%, p.i. (2 h) g G-CSF (5 g/kg/d s.c.) until ANC > 5,000/L Fluid balance: I > O + 400 ml/m2/12h 0.5 mg/kg (max. 20 mg) furosemide i.v. _____ _____ _____ _____ _____ _____ _____ _____ _____ ml/m2/12h _____ _____ _____ _____ _____ _____ _____ _____ _____ mg i.v.
Date: ________ Supportive: Drug Date Signature: Physician 1_______________ Physician 2 _______________ 1. _______________________ 2. _______________________ 3. _______________________ 4. _______________________
ALL IC-BFM 2002
ALL IC-BFM 2002 : Maintenance Therapy

DOB:
BC*
Appendix 3.0.i
Cycle :
Name:
Weight:
kg Height:
cm
BSA:
m2
MTX p.o. 20 mg/m /wk
6-MP p.o. 50 mg/m /d (day: 1 70)

4 5 6 7 8 9 10
Week
Date
MTX mg/wk
6-MP mg/d
TMP/SMZ 5/25 mg/kg p.o. 3 consecutive days per wk Dose: ______ /______ mg Day: _____ /_____ / _____
WBC /L
Hg
g/dL
PLT /L
* Blood chemistry: ALT U/L AST U/L Bili mol/L ALP U/L Crea mol/L
i.v. ATB (n days) RBC transf.(n) PLT transf. (n)
Fracture (? wk)
Osteonecrosis (yes/no)
Signature
ALL IC-BFM 2002
Appendix 3.1
Leucovorin Rescue Plan

Principles: Immediate MTX24 / 42 / 48 level measurement. Table 1: Regular Plasma MTX Levels & Standard LCV Rescue
MTXhour MTX24 MTX36 MTX42 MTX48 mol/L < 150 < 3.0 1.0 0.4 Rescue at: [h] Leucovorin i.v. [mg/m2]
42 48 54
15 15 15
Management guidelines for non-regular MTX elimination Forced diuresis up to 4,500 ml/m2/24h. Strict fluid balance control q 6 h (q 3 h); Cave: fluid overload (furosemide i.v. as needed). MTX level q 6 h. Immediate MTX36 level measurement only if MTX24 > 150 mol/L or when impaired MTX elimination is clinically
suspected, otherwise together with MTX42. Start of LCV rescue: as soon as increased MTX36 /42 level is available (Tab. 2). MTX42 1 to < 5.0 mol/L or MTX48 > 0.4 mol/L
Table 2: LCV Rescue in Case of Disproportionately High Plasma MTX Levels

LCV i.v. q 6 h until MTX 0.25 mol/L Dosage: according to Diagram for LCV Dosage by MTX Level (Fig. 1)- vide infra, corresponding to MTX value assessed 6 h earlier MTX42 > 5.0 mol/L LCV i.v. q 6 h until MTX 5.0 mol/L Dosage: LCV [mg] = MTX [mol/L] x weight [kg], See section 2.2.3.2 (p 58) & section 3.10 (p 135) corresponding to MTX value assessed 6 h earlier
Cave: Because of calcium content, a single LCV dose > 20 mg/kg should be administered via i.v. infusion over 1 h. Salvage with carboxypeptidase G2 (CPD G2): by availability. See section 2.2.3.2 (p 58) & section 3.10 (p 135).
Fig. 1: Diagram for LCV Dosage by MTX Level

MTX [mol/L]
5 4 3 2 1 0.25 0
75 mg / m2 60 mg / m2 45 mg / m2 30 mg / m2 15 mg / m2
NO RESCUE 24 36 42 48 54 60 66 72 78 84 90 96
Time after start of MTX [h]
APPENDIX 3.2
THERAPY-TOXICITY DOCUMENTATION
ALL IC-BFM 2002
Acute - Toxicity Form
Appendix 3.2.a
Pt Initials (Surname / Name): ______ DOB: ___/___/___d/m/y
UPN:
RG:
SR
IR
HR
2A
2B
Acute Toxicity During / After ALL IC- BFM 2002

Protocol I: Protocol mM: 1. 1. Phase 1 1.MTX Phase 2 2.MTX 3.MTX 4.MTX 1. Phase 1 Phase 2 Protocol I': Protocol M: 2. HR-2' Block 1. 2. 3. Protocol III: Phase 1 1.MTX Phase 2 2.MTX 1. 3.MTX 4.MTX
2. HR-1' Block 2. Protocol II:
2. HR-3' Block Phase 2
Phase 1
Start of therapy block/phase: __ __ . __ __ . __ __ d/m/y
End of therapy block/phase: __ __ . __ __ . __ __ d/m/y
Please check off appropriate box for each parameter (maximal toxicity during & after block until start of next phase)
Classification According To NCI CTC, Modified By GPOH
Grade
General condition
0
normal activity none < 38 none 0 none none
1
mild impairment mild 38 39 adequate food intake 1 painless ulceration, erythema 2-3
2
age-related activities strongly limited pathogen not identified, IV antibiotics > 39 40 markedly decreased food intake 25 painful ulceration, can still eat 4 6 or night stools or light cramps > 1.5 3.0 x N > 2.5 5.0 x N > 1.5 3.0 x N 3.0 10.0 macroscopic w/o clots 40 59
3
bedridden, in need for nursing pathogen identified IV antibiotics > 40 < 24 h almost no food intake 6 - 10 painful ulceration, cannot eat 7 9 or incontinence or strong cramps > 3.0 10.0 x N > 5.0 20.0 x N > 3.0 6.0 x N > 10.0 macroscopic with clots 20 - 39
4
intensive care, very sick septic shock > 40 24 h TPN necessary > 10/TPN necessary TPN required due to stomatitis ? 10 or bloody diarrhea or TPN required > 10.0 x N > 20.0 x N > 6.0 x N nephrotic syndrome transfusion required 19 hypotension, ventr. arrhyth., defibrillation severe / refractory cardiac insufficiency 15% coma, seizures
Infection
Infection Fever (C)
Gastrointestinal toxicity
Nausea Vomiting (in 24 h) Stomatitis Diarrhea (stool frequency/day)
Liver toxicity
S- bilirubin S- ALT/ S- AST normal for age normal for age normal for age none none 90 none normal for age 30% none > N 1.5 x N > N 2.5 x N > N 1.5 x N < 3.0 microscopic 60 - 89
Renal toxicity:
Creatinine Proteinuria (g/L) Hematuria Creatinine clearance 2 (ml/min/1,73m )
Cardiac toxicity
Arrhythmia Cardiac function Echo-CG: LVSF asymptomatic, no therapy EF < 20% from baseline value 24% - < 30% transient lethargy recurrent / persistent, no therapy EF 20% from baseline value 20% - < 24% somnolence < 50% of the day, moderate disorientation severe paresthesias and/or mild weakness therapy required mild cardiac insuff., therapeutically compensated > 15% - < 20% somnolence 50% of the day, disorientation, hallucinations unbearable paresthesias, marked motor deficits
Neurologic toxicity
Central neurotoxicity
Peripheral neurotoxicity, Myopathy
none
paresthesias and/or decreased tendon reflexes
paralysis
Skeletal toxicity: acute & delayed

Osteonecrosis none asymptomatic and detectable only by imagining techniques symptomatic with decreased function, but no limitations in everyday living symptomatic and restrictions in everyday living symptomatic, crippling
Notes/other complications: (severe & life-threatening complications as well as extraordinary accidents & toxic deaths must be notified within 24 72 h to National Study Coordinator, and reported without delay to him/her and National Data Manager on the SAE Form)
Other toxicity: _______________________________________________________________________________________________

Abbreviations: N normal for age EF ejection fraction LVSF left-ventricle shortening fraction Date: _____/_____/_____ d/m/y Please send copy to National Study Coordinator & National Data Manager Stamp: Signature: _____________
ALL IC BFM-2002
Acute-toxicity Instructions
Appendix 3.2.b
Instructions for Filling the Acute-Toxicity Form

One Toxicity Form should be filled for each therapeutic part: Phase 1 & 2 of Protocol I/I'/II/III, each MD/HD MTX in Protocol mM/M, every HR block (HR-1', HR-2', HR-3') & its repetition. The part in question must be ticked in the Toxicity Form. The first day of treatment according to a specific part of a protocol is considered as the date of start of that part. Similarly, the end-of-therapy date of a specific part of a protocol is the same as the last day of treatment with that part. However, all toxicities occurring until the start of the next therapy element/part thereof must be added to the debit of the just outgoing one. For example: The first day of therapy according to I/1 is 01.11.2002 = Date of start of I/1 = 01.11.2002. The last day of therapy according to I/1 is 04.12.2002 = Date of end of I/1 = 04.12.2002. The first day of therapy according to I/2 is 07.12.2002 = Date of start of I/2 = 07.12.2002. On the Toxicity Form for I/1 all reportable toxicities seen through 06.12.2002 should be recorded. In each observation period the highest degree of toxicity observed for a given parameter should be recorded (reported). Only results of investigations carried out during the observation period will be reported. Earlier or later observations whatsoever will not be included. The table in Appendix 3.2.a is a shortened version of selected parameters of non-hematologic toxicity derived from the National Cancer Institute Common Toxicity Criteria (NCI CTC) as adopted by SIOP and modified by the German Society of Pediatric Oncology/Hematology (GPOH). For other parameters not listed in the table one can refer to the widely accessible original document. However, not all parameters will be reported. For example, acute hematologic toxicity is routinely recorded in the patient's file, and serves for steering chemotherapy (entry criteria for commencing a therapy element or its part, dosage modification of 6-MP/MTX during interim maintenance and post-intensive long-term maintenance therapy, etc). It may also determine supportive therapy, first of all substitution with blood components, or guide the need for and duration of antimicrobial therapy, and so forth. Acute hematologic toxicity is therefore not liable to notification in this trial, except for drug-induced irreversible SAA. On the other hand, complications consequent on chemotherapy-induced BM failure, e.g. infection or hemorrhage, should be reported. This is done on the Acute-Toxicity Form (Appendix 3.2.a) as appropriate, i.e. either in the body or the footnote of that Form. Other acute non-hematologic adverse events that are serious, life threatening or that interfere with the fluent flow and structure of the basic treatment, e.g. acute pancreatitis, anaphylaxis, ARDS, etc, must be immediately notified to the national study coordinator and properly reported in the footnote of the Acute-Toxicity Form. In addition, if severe (grade 3/4) or fatal they should be also reported on the SAE Form (Appendix 1.4). Secondary leukemia or MDS is a matter of late effects, and should be reported as such on the Follow-up Form (Appendix 1.3.d) & Late-Effects Follow-up Form (Appendix 3.3). It is recognized that the reference values (so-called normal range) may vary between labs for different populations, techniques, equipment and reagents. It is recommended to employ standard lab methods. For the purpose of toxicity grading however, an absolute value falling outside the normal range must be compared with the upper or lower limit of normal as appropriate, i.e. depending on whether the usual pathology of a given parameter is that of increase or decrease, respectively. The result is then expressed as a ratio of the measured absolute value and the ULN or LLN, thus giving a relative value to be used for the assessment of the degree of toxicity.
SELECTED PARAMETERS General Condition See table- Appendix 3.2.a. Infection All infections (bacterial, viral, fungal & protozoan) regardless of the pathogen are included. Fever See table- Appendix 3.2.a. Nausea / Vomiting / Diarrhea See table- Appendix 3.2.a. Stomatitis Stomatitis means any damage to oral mucosa as a result of chemotherapy. Pain in the mouth, ulcerations of and even bleeding from mucous membranes are also included in this category. Bilirubin For the first month of life special guidelines apply. Refer to a textbook of pediatrics for reference values. For children > 1 month of age and adults: < 17 mol/L (< 1 mg/dL). N = ULN = Upper Limit of Normal = 17 mol/L
GOT = AST / GPT = ALT For assessment of the grade of toxicity both parameters should be considered separately. The higher value of GOT or GPT determines the toxicity grade. Table 3: Normal Range of GOT (AST) & GPT (ALT) by Age Newborn Children & Adults GOT = AST [U/L] 15 60 8 20 GPT = ALT [U/L] 5 25 8 20 N = ULN = Upper Limit of Normal Creatinine Table 4: ULN of Plasma Creatinine by Age [mol/L] < 106 Newborn th < 44 Till end of 5 yr < 88 Till end of 10th yr < 106 > 10 yr N = ULN = Upper Limit of Normal (mg/dL) < 1.2 < 0.5 < 1.0 < 1.2
Proteinuria / Hematuria See table- Appendix 3.2.a. Creatinine clearance (CLcr) This corresponds essentially to glomerular filtration rate (GFR). It can be assessed either by the classic technique of CLcr requiring 24h-urine collection or by radionuclide scans using 51Cr-EDTA/99mTc-DTPA. Alternatively, it is practical to estimate CLcr (GFR) from body height (length) and plasma creatinine according to the formula of Schwartz et al., which was originally proposed for children > 6 months of age (Schwartz GJ et
al. 1976)(84), and later (1984, 1985) developed by the same investigators for full-term newborns and infants, as well as for adolescents: CLcr [ml/min/1.73 m ] =
2
K1 x Height [cm] Plasma Creatinine [mg/dL]
K2 x Height [cm] Plasma Creatinine [mol/L]
The constant of proportionality in the numerator is related to creatinine excretion per unit body size, and depends on age, reflecting changes in muscle mass that occur during childhood. Table 5: Constant of Proportionality by Age (Schwartz Formula) Age [yr] K1 K2 = 88.18 x K1 Full-term neonates & infants < 1 0.45 39.7 Children 1 13 0.55 48.5 M adolescents 14 21 0.70 61.7 F adolescents 14 21 0.57 50.3 Arrhythmia Grade 1 Grade 2 Grade 3 Grade 4 Isolated remarkable ECG findings not requiring therapy, e.g. extrasystoles Recurrent remarkable ECG findings not requiring therapy, e.g. repetitive premature systoles Serious arrhythmia necessitating therapy, e.g. atrial fibrillation or flatter Severe arrhythmia involving the ventricles or leading to hypotension
Cardiac Function LVEF = Left-Ventricle Ejection Fraction (value derived from echocardiogram) LVSF = Left-Ventricle Shortening Fraction (value derived from echocardiogram) CHF = congestive heart failure Grade 1 Grade 2 Grade 3 Grade 4 EF decreased by < 20% from pre-treatment value EF decreased by > 20% from pre-treatment value Cardiac insufficiency requiring therapy and responding to it Heart failure refractory to treatment
Central & Peripheral Neurotoxicity See table- Appendix 3.2.a. Osteonecrosis Grade 1 Incidental finding Grade 2 Remarkable difficulties are apparent, with only slightly limited function, e.g. in sport, but without restrictions in routine activities of daily living Grade 3 Remarkable problems significantly limiting daily activities Grade 4 Significantly impaired joint or limb function that may require joint replacement, crutches, wheel chair etc.
ALL IC-BFM 2002
Appendix 3.3
Late-Effects Follow-up Form

First Proposal for FU of Patients with ALL
Elaborated in cooperation between leadership of ALL-BFM 2000 trial, LESS, ELTEC (I-BFM-SG) & Quality-of-Life-&-Late-Effects Project
Pt's Initials (Surname / Name): ____________________
Date___.___.___ End of Treatment (Maintenance) Complete physical exam.+ testicles Neurology CBC + diff. LDH Blood chemistry1 Renal function2 Viral serology3 Ab titers4 Endocrinology Percentiles5 Tanner / breast abnorm. / volume of testicles Serum parameters6 Spermiogram Ophthalmology US thyroid fT3, fT4, TSH7 ECG/ (stress)-Echo-CG BMD Neuropsychologic tests (motor, coordination, cognitive domain): from 6. yr of age FU after radiotherapy x x x x x x x x x 1. yr 20__ 2. yr 20__ After End Of Treatment 3. yr 4. yr 20__ 20__ q 4 months q 4 months q 4 months 5. yr 20__ q 6 months q 6 months q 6 months - 10. yr -20__ x x x
Diagnostics to rule out recurrence monthly q 3 months q 3 months monthly monthly q 3 months q 3 months q 3 months q 3 months
FU & late-effects diagnostics x q 4 months q 6 months x x x q 6 months x q 6 months x x x x x x x x
in case of remarkable deviations in pubertal development once after 18. yr x x x x x q 2 yr x x x x
q 1 yr according to APRO guidelines Second Malignancies (increased risk for developing brain tumors) the most common second malignancy in ALL: brain tumors 6 10 yr after Dx of ALL
1 2
CRP, ESR, bilirubin, AST, ALT, -GT, ALP, LDH, -amylase, ferritin, immunoglobulins Blood: phosphate, calcium, magnesium, sodium, potassium, creatinine, bicarbonate Urine: urinalysis, phosphate, calcium, creatinine
3 4 5 6 7
HBV, HCV, CMV, HIV Diphtheria, tetanus X-ray of left hand/wrist (bone age) LH, FSH, Prolactin, Estradiol, (stimulation tests, if need be) Only after cranial radiotherapy
APPENDIX 4
4.0 IMMUNOPHENOTYPIC CLASSIFICATION OF ACUTE LEUKEMIAS
ALL IC-BFM 2002
Appendix 4.0
Immunophenotypic Classification of Acute Leukemias General points, conventions & definitions

Surface expression is considered, unless the prefix intra is added. If expression in the membrane or intracellular or both is considered for the definition, the prefix intra is in parentheses. Examples: CD3pos means surface positivity regardless of the intracellular expression; intraIgM means intracellular expression regardless the membrane; (intra)CD79a means expression of CD79a on the membrane, intracellularly or both. The positivity cut-off is 20% of blasts. Cytometry gates are set at the optimal population of cells using optical scatter properties (FSc & SSc).
Acute lymphoblastic leukemia

Category proB ALL B c ALL precursor preB ALL Definition CD10neg CD20neg CD10pos intraIgMneg intraIgMpos 2 or 3 of: CD19pos, (intra)CD79apos, CD22pos CD3neg, intraCD3neg, neg and neg either pos or pos Typical findings CD10pos HLADRpos, intraTdTpos, CD7neg
B precursor (shared features)
aberrant My Agsneg, CD20pos, intraTdTneg, mature B may be CD10pos Mature B ALL has characteristically L3 morphology. True mature B ALL cases with L1 or L2 are rare but do occur typical mature B translocations [t(8;14), t(8;22), t(2;8)] are found in these blasts, and genetics should be solicited before the final decision is made. Simultaneous positivity of both and usually indicates improper handling of the specimen, mostly low transport temperature. Intracellular or expression is not considered for classification in ALL IC-BFM 2002. proT ALL CD2neg CD5neg CD8neg preT ALL CD2pos and/or CD5pos and/or CD8pos CD4pos & CD8pos, CD1apos [Some cases intermediate T ALL T lineage may be CD3pos ] pos neg mature T ALL CD3 CD1a TCRpos T ALL TCRpos TCRpos T ALL TCRpos T lineage (intra)CD3pos , CD7pos (shared features)
Acute biphenotypic (hybrid) leukemia (AHL)

Definition: AHL is an acute leukemia with blasts scoring > 2 points (according to the scoring table below) for myeloid lineage and simultaneously >2 points for B or T lineage.
Scoring B lineage T lineage My lineage points 2 (intra)CD79a, (intra)CD3, TCR, TCR intraMPO intraIgM, (intra)CD22 1 CD19, CD10, CD20 CD2, CD5, CD8, CD10 CD13, CD33, CD65, CD117 0.5 intraTdT, CD24 intraTdT, CD7, CD1a CD14, CD15, CD64 Notes: EGIL scoring is adopted in its modified version (Bene, Castoldi et al. 1995; Bene, Bernier et al. 1998). This scoring system is not intended for the diagnostic distinction between ALL and AML. In doubtful cases, look at the definitions first and see if the necessary criteria are met; don't compare the absolute score values. Frequently, the cells clearly belong to one lineage, based on the pattern of expression of multiple antigens, but the case is assigned to AHL, because the aberrant antigens reach a score of > 2.0. In such cases, the cytometrist should always include the primary lineage of the blasts and the respective reasoning. In accordance with the AIEOP LLA-2000/ALL-BFM2000, true AHL cases should be adequately reported and can receive the ALL-focused treatment within ALL IC-BFM 2002 as study-patients.
Acute undifferentiated leukemia (AUL)

Definition: Acute leukemia that is unclassifiable using morphology, immunophenotyping and cytochemistry. Note: This is an extremely rare entity. Non-hematologic malignancies must be considered and ruled out.
Acute myeloid leukemia (AML)

Definition At least 2 of the following: intraMPOpos, CD13pos, CD33pos, CD65pos and/or CD117pos (intra)CD3neg, (intra)CD22neg, (intra)CD79aneg
Diagnostic delineation of ALL vs. Non-Hodgkin Lymphoma

Cases with lymphoblasts >=25% in BM qualify for ALL, and should be managed within ALL IC-BFM 2002, except for mature B-ALL, which must be treated as such. Cases with blasts < 25% in BM are considered as NHL, and must be handled as such outside ALL IC-BFM 2002.
I-BFM mini-mini Project

Participants and observers are asked to use the set of combinations following the I-BFM minimini guidelines http://clip.webpark.cz/minimini.html These combinations, in addition to the goals of I-BFM mini-mini Project, are also helpful in differential diagnostics. You may also use the email conference of the I-BFM mini-mini Project http://clip.webpark.cz/minimini/conference.html to get an insight of other colleagues.
References
ALL-BFM 2000: Immunologische Klassifizierung der akuter Leukmien (Anhang 4.0). Bene M C., Bernier M et al.: Blood 92 (2): 596-9; 1998. Bene MC., Castoldi G et al.: Leukemia 9 (10): 1783-6; 1995.
Questions & consulting

You can consult individual cases with the national reference lab or you can email your question or comment to the author of these guidelines (Ondrej.Hrusak@lfmotol.cuni.cz).
APPENDIX 5
5.0 PARTICIPATING COOPERATIVE / NATIONAL GROUPS
Participating Cooperative / National Groups

Vice-Coordinator:
Dr. Cecilia Riccheri OHiggins 2008 Piso 5
0
National Coordinators, Data Managers and Reference Laboratories Data Manager:

Dr. Francisco Javier Last iri Statistic Department of GAT LA Pacheco de Melo 3081 (CP 1425) Cap. Federal Argentina FAX ! E-mail: webmaster@gatla.org.ar +54-11-4806 8457 Argentina FAX +54-11-4308 5325 ! +54-11-4308 4300 E-mai l: jorro98@hot mail.com 12 45 Buenos Aires Immunology Department Dr. Jorge G. Rosi Hospital de Pediat ria Juan P. Garrahan
ALL IC-BFM 2002
State
National Coordinator:
National Reference Laboratory for Immunophenotyping:
Arge ntina (CP 1428) Capital Federal-Buenos Aires Argentina FAX +54-11-4784 4115 +54-11-4784 4115 ! E-mail: mcriccheri@int ramed.net.ar Dr. Maria Sara Felice Hospital de Pediatria Juan P. Garrahan Hematology and Oncology Department 12 45 Buenos Aires Argentina FAX +54-11-4308 5325 +54-11-4308 4300 (Int 1301;1597;1417) ! E-mail: mfelice@dd.com.ar Prof. Dr. Carmen Salgado Univ. de Chile, Hospital Exequiel Gonalez Cortes Hemato-Oncology Division Copan 1803, Vitacura Santiago Chile FAX +56-2-556 8840 +56-2-242 1140 ! E-mail: csalgado@mannquehue.net Dr. Miljenka Smokvina Childrens Clinic Kantrida Istarska 43 HR-51000 Rijeka Croatia FAX +385-51-623 126 +385-51-659 111 ! E-mail: miljenko.smokvina@ri.tel.hr Chile FAX +56-2-735 0725 +56-2-239 2765 ! E-mail: fsferrei@vtr.net Dr. Ranka Femenic Childrens Clinic Salata Salat a 4 HR-10000 Zagreb Croatia FAX +385-1-492 0017 +385-1-455 2333 (ext 371) ! E-mail: ranka.femenic-kes@zg.hinet .hr Santiago Prof. Dr. Myriam Campbell Universidad de Chile, Roberto del Rio Hospital Hemato-Oncology Division Gral Pedro Dartnell 1526, Nunoa Dr. Maria Elena Cabrera Universidad de Chile Hospital del Salvador
Dr. Eduardo A. Dibar
Hospit al It aliano de Buenos Aires
Pediat ric Hematology-Oncology Div.
Gascon 450
1181 Cap.Fed.- Buenos Aires
Argent ina
FAX +54-11-4958 4093
! +54-11-4658 6923 E-mai l: eduardo.dibar@hospitalitaliano.org.ar
Chile
Prof. Dr. Myriam Campbell
Universidad de Chile, Roberto del Rio Hospital
Hemat o-Oncology Division
Gral Pedro Dartnell 1526, Nunoa
Avda La Escuela 930, Las Condes Santiago Chile FAX +56-2-225 2031 ! +56-2-211 9246 E-mai l: mcabrera@mi-mail.cl Doc. Dr. Drago Batinic Clinical Hospital Cent er Rebro Kispat iceva 12 HR-10000 Zagreb Croatia FAX ! +385-1-238 8888 E-mai l: drago.bat inic@zg.tel.hr
Santiago
Chile
FAX +56-2-735 0725
! +56-2-239 2765 E-mai l: fsferrei@vtr.net
Croatia
Prof. Dr. Josip Konja
Childrens Clinic Salata
Salata 4
HR-10000 Zagreb
Croatia
FAX +385-1-492 0017
Appendix 5.0
! +385-1-492 0017/385-99-424 691 E-mai l: josip.konja@zg.tel.hr
State
Dr. Srdana Culic Childrens Clinic Split Spinciceva1 HR-21000 Split Croatia FAX +385-21-556 590 +385-21-556 111 ! E-mail: srdjana.culic@st.tel.hr Dr. Yahia Jabali Regional Hospit al Dept. of Pediatrics B.Nmcov 54 370 87 esk Budjovice Czech Republic FAX +420-38-787 6302 +420-38-787 6376 ! E-mail: jabali@nemcb.cz +420-2-2443 2201 ! E-mail: alena.vrzalova@lfmotol.cuni.cz FAX +420-2-2443 2220 Czech Republic 150 06 Praha 5 V valu 84 2nd Dept . of Pediatrics Universit y Hospital Motol Alena Vrzalov, MSc Dr. Ondrej Hrusak University Hospit al Motol Institute of Immunology Laboratory for Flow Cytometry V valu 84 150 06 Praha 5 Czech Republic FAX +420-2-2443 2084 ! +420-2-2443 5969 E-mai l: ondrej.hrusak@lfmot ol.cuni.cz Dr. Margaret NG Prince of Wales Hospital T he Chinese Universit y of Hong Kong Department of Anatomical and Cellular Pathology Haematology Laboratory Shatin +852-2649 7859 Hong Kong FAX +852-2602 3185 ! +852-2632 2179 E-mai l: margaretng@cuhk.edu.hk Dr. Zsuzsanna Jakab Semmelweis Medical University 2nd Department of Pediatrics T uzolt u. 7-9 1094 Budapest Hungary FAX +36-1-217 4404 +36-1-215 1380 ! E-mail: jakab@gyer2.sote.hu Nagyerdei krt. 98 4032 Debrecen Hungary FAX +36-52-417 631 ! +36-52-431 956 E-mai l: Dr. Laszlo Muszbek Debrecen Medical University
Vice-Coordinator:
Data Manager:
ALL IC-BFM 2002
Czech Republic Dr. Jan Star
University Hospital Motol
2nd Dept. of Pediatrics
V valu 84
150 06 Praha 5
Czech Republic
FAX +420-2-2443 2220
! +420-2-2443 2201 E-mai l: jan.stary@lfmotol.cuni.cz
Hong Kong Queen Mary Hospit al Department of Pediatrics Hong Kong FAX +852-2855 4849 +852-2855 3453 ! E-mail: syha@hkucc.hku.hk FAX Shatin Hong Kong Prince of Wales Hospital
Dr. Chi-Kong LI Dr. Shau-Yin HA
Ms Heidi Wong T he Chinese University of Hong Kong Cancer Centre, Room G17
Prince of Wales Hospital
The Chinese Universit y of Hong Kong
Depart ment of Pediatrics
Shatin
Hong Kong
FAX +852-2649 7859
! +852-2632 1029 E-mai l: ckli@cuhk.edu.hk
+852-2632 1029 ! E-mail: heidiwong2001@yahoo.com.hk
Hungary Semmelweis Medical University 1st Department of Pediatrics Bkay J. u. 53 1083 Budapest Hungary FAX +36-1-303 6022 +36-1-334 3186 ! E-mail: benyo@gyer1.sote.hu
Dr. Edina Magyarosy
Dr. Gbor Beny
Heim Pal Childrens Hospital
Hemat o-Oncology Department
lloi u. 86
1089 Budapest
Hungary
FAX +36-1-459 9154
Appendix 5.0
! +36-1-459 9108 E-mai l: tapolcai@sztaki.hu
State
Prof. Rina Zaizov Schneider Childrens Medical Center of Israel Pediatric Hemat ology Oncology Pet ah-T ikva 49202 Israel FAX +972-3-925 3042 +972-3-925 3669 ! E-mail: dnaomi@clalit.org.il Statistics: Prof. David M. Steinberg T el Aviv University Dept . of Stat istics and OR T el Aviv 69978 Israel FAX +972-3-640 8035 ! E-mail: dms@post.t au.ac.il +972-3-640 9357 Dr. Drorit Luria, PhD Schneider Childrens Medical Cent er of Israel Pediat ric Hematology Oncology Immunophenotyping Laboratory Kaplan 14 Petah-Tikva 49202 Israel FAX +972-3-925 3042 ! +972-3-925 3669 E-mai l: dnaomi@clalit.org.il Dr. Anna Pituch-Noworolska University Childrens Hospital Department of Clinical Immunology ul. Wielicka 265 30-663 Krakw Poland +48-81-747 7220 +48-81-718 5530 ! E-mail: dkrasn@dsk.lublin.pl Dr. Nicole Brockhorst Fundacin Peluffo Guigues Bulevar Artigas 1556 CP: 1600, Montevideo Uruguay FAX +598-2-708 3095 +598-2-708 3095 ! E-mail: nbrock@adinet.com.uy fpghop@adinet.com.uy FAX +48-12-658 9730 ! +48-12-658 9730 E-mai l: mipit ucha@cyf-kr.edu.pl Dr. Hugo Giordano Asociacion Espaola Bulevar Artigas 1465 Montevideo Uruguay FAX +598-2-408 7588 ! +598-2-408 7427 E-mai l: hgiordano@asesp.com.uy giordano@montevideo.com.uy +972-3-925 3669 ! E-mail: dnaomi@clalit.org.il FAX +972-3-925 3042 FAX ! E-mai l: e-rosent@sheba.healt h.gov.il Israel Israel Petah-Tikva 49202 T el Hashomer 52621 Pediatric Hematology Oncology Hematological Institut e, FACS laboratory Schneider Childrens Medical Center of Israel Sheba Medical Center Ms Dina Kugel Dr. Et i Rosent hal
Vice-Coordinator:
Data Manager:
Israe l
Dr. Batia Stark
Schneider Childrens Medical Center of Israel
Pediat ric Hematology Oncology
ALL IC-BFM 2002
Petah-Tikva 49202
Israel
FAX +972-3-925 3042
! +972-3-925 3669 E-mai l: dnaomi@clalit.org.il
Dr. Shai Izraeli
Sheba Medical Center
Pediat ric Hematology Oncology
Tel Hashomer 52621
Israel
FAX +972-3-530 2377
! +972-3-530 2327 E-mai l: sizraeli@post.tau.ac.il
Poland Department of Pediatric Hematology and Oncology ul. Szpit alna 27/33 60-572 Poznan Poland FAX +48-61-847 4356 +48-61-847 4356 ! E-mail: bmt5641@sk5.usoms.poznan.pl Poland FAX ul. Chodzki 2 20-093 Lublin and Oncology
Prof. Dr. med. Jerzy Kowalczyk
Dr. Malgorzata Kaczmarek-Kanold
Dariusz Krasnodebski Department of Pediatric Hematology
Depart ment of Pediatric Hematology
and Oncology
ul. Chodzki 2
20-093 Lublin
Poland
FAX +48-81-747 7220
! +48-81-718 5520 E-mai l: jkowalcz@dsk.lublin.pl
Uruguay
Dr. Luis Castillo
Fundacin Peluffo Guigues
Bulevar Artigas 1556
CP: 1600, Montevideo
Uruguay
FAX +598-2-708 3095
! +598-2-708 3095 E-mai l: lcast@adinet.com.uy
Appendix 5.0
fpghop@adinet.com.uy
State
Dr. Eva G. Svarch Inst ituto de Hematologia e Immunologia Ave San Francisco y calle E Altahabana 10 800 La Habana Cuba FAX +53-7-44334 +53-7-578 268 ! E-mail: esvarch@hemato.sld.cu eva_svarch@hotmailcom Prof. Dr. Nazan Cet ingul Universit y of Ist anbul, Cerrahpasa Medical School Department of Pediatric Hematology/Oncology 34303 Aksaray - Istanbul T urkey FAX ! E-mail: Sergey Dyma Regional Oncologic Hospital Ped. Oncology-Hematology Dep. in Kiev Baggovut ovska-Str. 1a 04107 Kyiv Ukraine FAX +380-44-213 1646 +380-44-219 4982 ! E-mail: ped.oncol@ukrnet.net Jelena Lazic Universit y Childrens Hospital Dept . Hemat ology/Oncology T irsova 10 11000 Belgrade Yugoslavia FAX +381-11-684 672 +381-11-688 541 ! E-mail: dr.janic@eunet.yu Dr. Elena Kreminska Regional Oncologic Hospit al Ped. Oncology-Hemat ology Dep. in Kiev Baggovutovska-St r. 1a 04107 Kyiv Ukraine FAX +380-44-213 1646 ! +380-44-219 4982 E-mai l: ped.oncol@ukrnet.net Dr. Bojana Slavkovic Institute for Mother and Child Laboratory for Immunophenotyping Radoja Dakica 6-8 11070 Belgrade Yugoslavia FAX +381-11-697 232 ! +381-11-310 8177 E-mai l: bonaka2001@yahoo.com Dept. of Pediatric Oncology 35100 Bornova - Izmir Turkey FAX +90-232-362 4990 +90-232-388 1858 ! E-mail: cet ingul@med.ege.edu.t r Dr. Valentin Usatchenko Republican Childrens Hospital Hematology Depart ment in Krym Tyt ova-Str. 77 95000 Sympheropil Ukraine FAX +380-652-27 0477 ! E-mail: Dr. Dragan Micic Inst itute for Mother and Child Dept. Hematology Radoja Dakica 6-8 11070 Belgrade Yugoslavia FAX +381-11-697 232 +381-11-310 8245 ! E-mail: dr.micic@eunet .yu Dr. Hilmi Apak +53-7-578 268 ! E-mail: smachin@hemato.sld.cu FAX +53-7-44334 FAX +53-7-44334 ! +53-7-578 268 E-mai l: cmacias@hemato.sld.cu Cuba Cuba 10 800 La Habana 10 800 La Habana Ave San Francisco y calle E Altahabana Ave San Francisco y calle E Altahabana Instituto de Hematologia e Immunologia Instituto de Hematologia e Immunologia Sergio Machin Dr. Consuelo Macas
Vice-Coordinator:
Data Manager:
Cuba
Dr. Alejandro Gonzlez
Instituto de Hemat ologia e Immunologia
Ave San Francisco y calle E Altahabana
ALL IC-BFM 2002
10 800 La Habana
Cuba
FAX +53-7-44334
! +53-7-578 268 E-mai l: agonzalez@hemat o.sld.cu
ot ero@infomed.sld.cu
Turkey
Prof. Dr. Lebriz Yuksel Soycan
University of Istanbul, Cerrahpasa Medical School Ege University Medical School
Depart ment of Pediatric Hematology/Oncology
34303 Aksaray - Istanbul
Turkey
FAX +90-212-418 8834
! +90-212-530 0331 E-mai l: lebrizy@t urk.net
Ukraine
Dr. Svitlana Donska
Regional Oncologic Hospit al
Ped. Oncology-Hematology Dep. in Kiev
Baggovutovska-Str. 1a
04107 Kyiv
Ukraine
FAX +380-44-213 1646
! +380-44-219 4982 E-mai l: ped.oncol@ukrnet .net
Yugoslavia
Dr. Dragana Janic
University Childrens Hospital
Dept. Hematology/Oncology
Tirsova 10
11000 Belgrade
Yugoslavia
FAX +381-11-684 672/629 273
Appendix 5.0
! +381-11-629 273 E-mai l: dr.janic@eunet.yu

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APPENDIX 1

Diagnostics in ALL IC-BFM 2002

Day before Prot. Month 24 mM/M/1.HR' block

Reference center: Morphology (PB/BM/LP) Therapy Response & Remission Status

6 PB smears 6 BM smears 2 cytospin smears 6 PB 6 BM 6 BM

Immunophenotyping (DNA index, MRD)

1 PB + 1 BM smear 2 ml EDTA BM 5 ml EDTA PB 2 ml PB+BM* 2 ml BM 2 ml BM _ 2 ml BM

Molecular Genetics +MRD Diagnostics

1 PB + 1 BM smear 2 ml EDTA BM 5 ml EDTA PB

1 PB + 1 BM smear 3 ml heparin. BM 3 ml heparin. PB

10 ml EDTA BM if WBC < 2,000/L in PB _ _ _

ALL IC-BFM 2002

ALL IC BFM 2002

Previous treatment with corticosteroids or cytostatic agents: Previous treatment timing:

ALL treatment started at another department:

WBC / L: Platelets / L: Blasts (%): Hb (g/dL): . cm BSA: . m2

Date of 1. prednisone dose:

ALL IC-BFM 2002

CNS LEUKEMIA (initial):

yes yes yes yes

Cerebral mass: Retinal involvement: Cells in CSF / L: Blasts in CSF (%):

CNS status at diagnosis:

ORGAN INVOLVEMENT (initial):

Result: Result: Result: 2/3

ALL IC-BFM 2002

DAY 8 prednisone response:

Blast cell count / L: BM cellularity:

Normal Hypoplastic Aplastic no

Blasts in BM (%): Comments:

Patient alive Patient dead

Please send copy to National Study Coordinator

ALL IC-BFM 2002

ALL IC BFM 2002

Site of relapse: Remission achieved:

AML other tumor

Skeleton Heart CNS Kidney Liver Date of death:

Relapse Secondary malignancy Other:

Please send copy to National Study Coordinator

VARIABLES IN ALL IC-BFM 2002 DATABASE

INIT SEX DOB DOD ELIG CONOELIG

TCRA TCRB AHLT

Therapy Realization & Toxicity

3. Therapy-Flow & Toxicity Data UPN Group

ELE_NO ELE_PH ELESTART ELEEND BS DEV_TIM DEV_MED DEV_DOS

VAR. NAME DOREL R_BM R_CNS R_TESTIS R_OTHER DODEAD CODEAD

PH_DEAD DOSMN T_SMN DOLFU

Source of the graft

CODE LIST CYTOGENETICS

except t(4;11),t(11;19), t(9;11)

other than code 13

except Ph+ except t(2;5) except t(2;5) not in this list

ALL IC-BFM 2002 Severe-Adverse-Event Form

Surname:____________ Name:___________ Date of birth:____________

2.3 Informed Consent with Randomization to Arm SR-1 & SR-2

DISCUSSION PROTOCOL ON THERAPY ACCORDING TO ALL IC-BFM 2002

_______________________________ Patient's name

_____________________ Date of birth

Signatures ______________________________ Legal representative(s) and/or patient

Signatures ______________________________ Legal representative(s) and/or patient

Signatures ______________________________ Legal representative(s) and/or patient

APPENDIX 3.0 THERAPY FLOW SHEETS

ALL IC-BFM 2002

ALL IC-BFM 2002

Surname:______ Name:_ Date of birth:________

Physician 1_Physician 2 _

Physician 1_Physician 2 _

Physician 1_Physician 2 _