All Ic Append

APPENDIX 1

LOGISTICS & KEY DATA ON: PATIENT, DIAGNOSIS, THERAPY,

OUTCOME & TOXICITY

1.0 Logistics

1.1 Baseline-Data & Initial-Response Form

1.2 Follow-up Form

1.3 Variables in ALL IC-BFM 2002 Database

1.3.a Baseline Data

1.3.b Therapy

1.3.c Therapy Realization & Toxicity

1.3.d FU

1.3.e SCT

1.3 Add. Code List Cytogenetics

1.4 SAE Form

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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 Previous treatment with corticosteroids or cytostatic agents: no yes Previous treatment timing: within 4 weeks before diagnosis more than 4 weeks before diagnosis not known ALL � treatment started at another department: no yes , in

(place) DIAGNOSIS: Date of diagnosis: (dd/mm/yyyy)

Type of diagnosis: Primary disease Secondary malignancy Relapse BM at diagnosis: central review in local review (to be confirmed by reference lab)

Blasts in BM (%): Comments:

CBC at diagnosis: WBC / µL:

Platelets / µL:

Blasts (%):

Hb (g/dL): . Weight: . kg Height: cm BSA: . m2 Date of 1. prednisone dose: (dd/mm/yyyy) 1/3

ALL IC-BFM 2002 Appendix 1.1 CNS LEUKEMIA (initial): no yes Cerebral mass: no yes Blasts in CSF: no yes Retinal involvement: no yes CSF contaminated with blood: no yes Cells in CSF / µL: Cranial nerve palsy: no yes Blasts in CSF (%): CNS status at diagnosis: 1 2 3 ORGAN INVOLVEMENT (initial): Hepatomegaly: no yes: cm below costal margin Splenomegaly: no yes: cm below costal margin Thymus / Mediastinum: no yes Testicles / Ovaries: no yes Other organ involvement: DIAGNOSTICS: Immunology: no yes, central in Result: yes, local (please add copy) DNA index: no yes, central in DNA index: . yes, local (please add copy) Cytogenetics: no yes, central in Result: yes, local (please add copy) Molecular (cyto)genetics:

BCR/ABL no pos. neg. non-evaluable yes, performed in Result:

TEL/AML1 no yes, performed in Result:

MLL/AF4 no yes, performed in Result: 2/3

ALL IC-BFM 2002 Initial-Response Form Appendix 1.1 DAY 8 � prednisone response: Date: (dd/mm/yyyy)

PB: no (not performed), reason: yes, central review in yes, local review (to be confirmed by reference lab)

WBC / µL: Blast cell count / µL:

Blasts in PB (%):

Pre-phase cumulative dose of prednisone (7 days): mg/m2

BM (optional): no (not performed)

yes, central review in yes, local review (to be confirmed by reference lab)

BM cellularity: Normal Blasts in BM (%): Hypoplastic Comments: Aplastic DAY 15: Date: (dd/mm/yyyy)

PB + BM: no (not performed), reason: yes, central review in yes, local review (to be confirmed by reference lab)

WBC / µL: Blast cell count / µL: BM cellularity: Normal Blasts in BM (%):

Hypoplastic Comments: Aplastic DAY 33: Date: (dd/mm/yyyy)

PB + BM: no (not performed), reason: yes, central review in yes, local review (to be confirmed by reference lab)

Blast cell count / µL: BM cellularity: Normal Blasts in BM (%):

Hypoplastic Comments: Aplastic

CR 1 achieved: yes no If no, date of CR 1: (dd/mm/yyyy)

Comments: Patient alive Patient dead Physician Date (dd/mm/yyyy) Signature Please send copy to National Study Coordinator 3/3


ALL IC � BFM 2002 Follow-up Form

National Study Coordinator: Address: Tel.: Fax:

Initials (Family name/First name) UPN Center Sex (M/F) Date of Birth (dd/mm/yyyy) / Risk group: SR-1 IR-1 HR-1 SR-2 IR-2 HR-2A

HR-2B RELAPSE: 1. 2. 3. Relapse Date: (dd/mm/yyyy)

Site of relapse: BM CNS Testicles Other:

Remission achieved: no yes Date: (dd/mm/yyyy) SECONDARY MALIGNANCY: Date: (dd/mm/yyyy) Type of secondary malignancy: ALL B-ALL AML NHL HD CNS tumor other tumor Other: LATE TOXICITY: Date: (dd/mm/yyyy) Site/Type: Skeleton Psychologic GIT Heart Sense organ Skin CNS Lungs Osteonecrosis Kidney Endocrine Osteoporosis Liver Hematologic Other: Patient dead: Date of death: (dd/mm/yyyy) Autopsy: no yes

Cause of death: Death in induction Relapse Death in CR Secondary malignancy SCT Other: Follow - up: Date of last follow-up: (dd/mm/yyyy)

Phase of protocol: Comments: 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 IC-BFM 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 Baseline Data 1. Baseline Variables VAR. NAME Code UPN UPN Use your own UPN Group GROUP 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

Initials INIT First letter Family name, First name Sex SEX 1=male, 2=female Date of birth DOB day/month/year Date of diagnosis DOD day/month/year Eligible for study ELIG no=1(observed pt), yes=2(protocol pt) Reason for ELIG=No 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)

Weight WEIGHT (kg) Height HEIGHT (cm) Body surface BS (m2) Previous treatment with Corticosteroids or cytostatic agents

PRETX 1=no, 2=yes

Previous treatment timing PRETIME 1=within 4 weeks before diagnosis 2=more than 4 weeks before diagnosis 9= not known

WBC at diagnosis (/µL) WBC % blasts (PB) BLA % BM blasts at diagnosis BM Platelets (/µL) PLT Hb (g/dl) HB CNS status CNS 1=CNS status 1 2=CNS status 2

3=CNS status 3 Cells in CSF (/µL) CSF_CELL Blasts in CSF (%) BLA_CSF CSF contaminated with blood 1=no, 2=yes, 9=no data Cerebral mass CM_INV 1=no, 2=yes, 9=no data Cranial nerve palsy CNP_INV 1=no, 2=yes, 9=no data

Splenomegaly SPL_INV 1=no, 2=yes, 9=no data Splenomegaly MEA_SPLE cm below costal margin Hepatomegaly HEP_INV 1=no, 2=yes, 9=no data Hepatomegaly MEA_LIV cm below costal margin Mediastinal mass MED_INV 1=no, 2=yes, 9=no data Testicular involvement GON_INV 1=no, 2=yes, 9=no data Karyotype t(4;11) T411 1=negative, 2=positive, 9=no data Karyotype t(9;22) T922 1=negative, 2=positive, 9=no data Other karyotypes 1 KARYO1 See code list cytogenetics Other karyotypes 2 KARYO2 See code list cytogenetics Hyper-/Hypodiploidy HYPDIP 1= <45 2=>50 BCR/ABL BCR 1=negative, 2=positive, 9=no data MLL/AF4 MLL 1=negative, 2=positive, 9=no data TEL/AML1 TEL 1=negative, 2=positive, 9=no data Immunophenotype IMMPHEN 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

TCR alpha/beta (required only if IMMPHEN = 4 or 5)

TCRA 1=negative, 2=positive 9=no data

TCR gamma/delta (required only if IMMPHEN = 4 or 5)

TCRB

1=negative, 2=positive 9=no data

AHL-Type (required only if IMMPHEN = 12)

AHLT 1=b-lineage, 2=t-lineage

Markers (percent positive cells in blast gate)

CD7 CD7 % CD2 CD2 % CyCD3 CYCD3 % Surface CD3 CD3 % CD19 CD19 % CD10 CD10 % CD33 CD33 % CD66c CD66C % DNA index DNAI WBC/µL on day 8 WBC_8 Blast cell count/µL on day 8 COBLA_8 WBC/µL on day 15 WBC_15 Blast cell count/µL on day 15 COBLA_15 BM day 8, % blasts BLA_8 BM day 15, % blasts BLA_15 BM day 33, % blasts BLA_33

Appendix 1.3.b Therapy 2. Therapy Data VAR. NAME Code Date of start of treatment DOSTR day/month/year Pre-phase cumulative dose of prednisone (mg/m2)

PDN_DOSE

Date of first IT-MTX DOMTX day/month/year Dose of HD-MTX HD_MTX 1=2g/m2, 2=5g/m2 CR1 achieved CR1 1=no, 2=yes Date of first complete remission DOCR1 day/month/year Timing of CR1 CR_PHASE 1=early (day 33), 2=late (>day 33) Date of start of maintenance DOSM day/month/year Date of end of treatment CHTEND day/month/year Radiotherapy RT 1=no, 2=yes Risk group RG 1=SR, 2=IR, 3=HR Date of randomization DORAND day/month/year Treatment assigned R_ASS 1=SR-1, 2=SR-2, 3=IR-1, 4=IR-2,

5=HR-1, 6=HR-2A, 7=HR-2B Treatment administered R_ADM 1=SR-1, 2=SR-2, 3=IR-1, 4=IR-2,

5=HR-1, 6=HR-2A, 7=HR-2B Cause of non-randomization CONORAN 1=clinical decision, 2=parent's refusal

of random, 3=error, 9=not known Cause of shift (if treatment administered differs from assigned)

COSHIFT 1=doctor refuses the arm, 2=parents refuse the arm, 9=not known

Appendix 1.3.c Therapy Realization & Toxicity 3. Therapy-Flow & Toxicity Data VAR. NAME Code UPN UPN use your own UPN Group GROUP 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

Treatment element

ID_ELE 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'

Element no ELE_NO Prot- II/III 1=1., 2= 2. 3=3. HR: 1=Block no 1 ...6=Block no 6

Element phase ELE_PH Prot I/II/III 1=phase 1, 2=phase 2 Prot M. 1 = 1.MTX, 2 = 2.MTX, ...

First day of the element ELESTART day/month/year Last day of the element ELEEND day/month/year Body surface (m2) BS Deviations in timing DEV_TIM 1=no, 2=yes Deviations in medication (replacement of drugs)

DEV_MED 1=no, 2=yes

Deviation in dosages DEV_DOS 1=no, 2=yes

Deviation: cause DEV_CAU 1=initial complications, 2=allergic reaction3=other toxicity, 4=relapse/death 4=other

Deviation: Description and cause DEV_NOTE General condition TX_GC NCI Grade 0-4, 9 = no data Infection TX_INF NCI Grade 0-4, 9 = no data Fever TX_FEV NCI Grade 0-4, 9 = no data Nausea TX_NAUS NCI Grade 0-4, 9 = no data Vomiting TX_VOM NCI Grade 0-4, 9 = no data Stomatitis TX_STOM NCI Grade 0-4, 9 = no data Diarrhea TX_DIAR NCI Grade 0-4, 9 = no data S- bilirubin TX_BILI NCI Grade 0-4, 9 = no data S- ALT/ S- AST TX_ALT NCI Grade 0-4, 9 = no data Creatinine TX_CREA NCI Grade 0-4, 9 = no data Proteinuria TX_PROT NCI Grade 0-4, 9 = no data Hematuria TX_HEMA NCI Grade 0-4, 9 = no data Creatinine clearance TX_CRCL NCI Grade 0-4, 9 = no data Arrhythmia TX_ARRH NCI Grade 0-4, 9 = no data Cardiac function TX_CARD NCI Grade 0-4, 9 = no data Echocardio: LV-SF TX_SG NCI Grade 0-4, 9 = no data Central neurotoxicity TX_CNEU NCI Grade 0-4, 9 = no data Peripheral neurotoxicity TX_PNEU NCI Grade 0-4, 9 = no data Osteonecrosis TX_OST NCI Grade 0-4, 9 = no data Other toxicity TX_OTH 1=no, 2=yes Notes/other complications TX_NOTE Other toxicity, description; Notes Appendix 1.3.d FU 4. FU Data VAR. NAME Code Date of first relapse DOREL day/month/year Site of relapse: BM R_BM 1=no, 2=yes Site of relapse: CNS R_CNS 1=no, 2=yes Site of relapse: Testis R_TESTIS 1=no, 2=yes Site of relapse: Other R_OTHER 1=no, 2=yes Date of death DODEAD day/month/year Cause of death CODEAD 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

Phase of death PH_DEAD 1=before start of therapy, 2=in induction before CR, 3=in first CR, 4=after relapse, 5=after 2nd tumor

Date of 2nd malignancy DOSMN day/month/year Type of 2nd malignancy T_SMN Text (C 20) Date of last follow-up DOLFU day/month/year

Appendix 1.3.e SCT 5. SCT Data VAR. NAME Code Eligible for SCT ELBMT 1=no, 2=yes, 9=not known Search for donor DONOR 1=no, 2=yes, 9=not known No of siblings SIBL Histocompatibility HISTO 1=no, 2=yes, 9=not known Date of HLA typing DOHLA day/month/year Date of SCT DOBMT day/month/year Phase of disease at Tx PBMT 1=in CR1, 2=not in CR (e.g. non-

responder) Type of SCT TBMT 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

Source of the graft SBMT 1=BM, 2=PBSC, 3=cord blood, 9=not known

Addendum 1.3

CODE LIST CYTOGENETICS

a la J. Harbott (Some codes are relevant only for AML or lymphoma)

-1 no data 0 no result 1 normal 2 t(9;22)(q34;11) 3 11q23 aberrations except t(4;11),t(11;19), t(9;11) 9 der(1q)

10 single-cell aberrations 11 t(1;19)(q23;p13) 12 t(4;11)(q21;q23) 13 t(8;14)(q24;q32), t(2;8), t(8;22) 14 14q11 aberrations 15 del(6q) 16 del(9p) 17 der(12p) 18 >50 19 t(11;19)(q23;p13) 20 t(12;21)(p13;q22) 21 t(8;21)(q22;q22) 22 t(15;17)(q22;q11) 23 inv(16)/t(16;16) 24 t(9;11)(p22;q23) 25 t(6;9)(p23;q34) 26 der(3q) 27 +4 28 +8 29 -5/5q- 31 -X/-Y 32 +12 33 i(17q) 34 t(1;22)(p13;q13) 35 complex >=3 aberrations 36 7p- 37 +21 50 7 (in general) 51 -7 (only) 52 -7 (+ additional) 53 7q- (only) 54 7q- (+ additional) 55 -7 unclear; e.g. +mar 60 1p 61 2p12 62 t(2;5)

63 der(3)(q27) 64 +7 65 der(7)(p22) 66 der(7)(q34~35) 67 8q24 other than code 13 68 del(10q) 69 t(11;14)(q13;q32) / der(11)(q13) 70 t(11;18) 71 Dup(12q) 72 del(13q) 73 del(14q) 74 t(14;18)(q32;q21) 75 der(14q32) 76 der(15q) 77 der(17p) 78 der(17q) 79 +18 80 der(18q) 81 der(22)(q11) except Ph+ 82 +X 83 der(2)(p23) except t(2;5) 84 der(5)(q35) except t(2;5) 85 t(5;14)(q35;q32) 99 random aberration 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: 4 ڤ 3 ڤ Event: onset: __________ end: __________ or continuation ڤ Cause of event Is the initial status of the patient or other disease responsible for this event? impossible to consider ڤ no ڤ improbably ڤ possibly ڤ probably ڤ yes ڤ Is there any relation between the event and a study medication? impossible to consider ڤ no ڤ improbably ڤ possibly ڤ probably ڤ yes ڤ Course of event no ڤ yes ڤ Death Autopsy performed ڤ Cause of death: ڤ primary disease ڤ complications of treatment ڤ other _____________ life-threatening event ڤ persistent or severe sequels ڤ necessity or prolongation of hospitalization ڤ 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 Patient & Parent Information

2.1 Informed Consent

2.2 Discussion Protocol on Therapy According to ALL IC-BFM 2002

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

2.4 Informed Consent with Randomization to Arm IR-1 & IR-2

2.5 Informed Consent with Randomization to Arm HR-1 & HR-2A

2.6 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 co-operation 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 Signature Date _______________________ ____________________________ Name of legal representative Signature Date _______________________ ____________________________ Name of physician Signature Date _______________________ ____________________________ Name of a witness 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. 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 2.4

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:



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 HR-2B, 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:



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 HR-2B, 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 6-mercaptopurine 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 (G-CSF) 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 triple-drug 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:



APPENDIX 3 3.0 Therapy Flow Sheets 3.0.a Global Therapy Scheme 3.0.b 1 Protocol I 3.0.b 1/1 Protocol I � Infusion Plan / Phase 1 3.0.b 2 Protocol I' 3.0.b 2/1 Protocol I' � Infusion Plan / Phase 1 3.0.b 1/2+2/2 Protocol I/I' � Infusion Plan / Phase 2 3.0.c 1 Protocol mM 3.0.c 1.1 Protocol mM � Infusion Plan 3.0.c 2 Protocol M 3.0.c 2.1 Protocol M � Infusion Plan 3.0.d Protocol II 3.0.d 1 Protocol II � Infusion Plan / Phase 1 3.0.d 2 Protocol II � Infusion Plan / Phase 2 3.0.e Protocol III 3.0.e 1 Protocol III � Infusion Plan / Phase 1 3.0.e 2 Protocol III � Infusion Plan / Phase 2 3.0.f Block HR-1' 3.0.f 1 Block HR-1' � Infusion Plan 3.0.g Block HR-2' 3.0.g 1 Block HR-2' � Infusion Plan 3.0.h Block HR-3' 3.0.h 1 Block HR-3' � Infusion Plan 3.0.i Maintenance Therapy

3.1 Leucovorin-Rescue Plan

3.2 Therapy � Toxicity Documentation 3.2.a Acute-Toxicity Form 3.2.b Acute-Toxicity Instructions

3.3 Late-Effects Follow-Up Form

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ALL IC-BFM 2002 Appendix 3.0.b 1/1 Protocol I/Phase 1

Name: Weight: kg Height: cm BSA: m2 DOB: d/m/y Start: ___/___/___ End: ___/___ /___ Day 1: LP 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: 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) Day 15: 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: U L-Asparaginase (E. coli, native, Fa. Medac) (5,000 U/m2/d) p.i. over 1h ( ) in 50 ml NaCl 0.9%

Day 22: 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%


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: 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%


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: 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. Prednisone � taper: Day 29-31: ( - ): mg mg mg p.o. Day 32-34: ( - ): mg mg mg p.o. Day 35-37: ( - ): mg mg mg p.o.

Dosage of Methotrexate IT: <1 1 2 ≥3 Age (yr) 6 8 10 12 mg Methotrexate IT

Date:_____________ Signature: Physician 1___________________Physician 2 ___________________

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ALL IC-BFM 2002 Appendix 3.0.b 2/1 Protocol I'/Phase 1

Name: Weight: kg Height: cm BSA: m2 DOB: d/m/y Start: ___/___/___ End: ___/___ /___ Day 1: LP 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: 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) Day 15: 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: U L-Asparaginase (E. coli, native, Fa. Medac) (5,000 U/m2/d) p.i. over 1h ( ) in 50 ml NaCl 0.9 %

Day 22: 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: mg Vincristine (1.5 mg/m2/d) i.v. (max. 2.0 mg/SD) ( )


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: 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. Prednisone � taper: Day 29-31: ( - ): mg mg mg p.o. Day 32-34: ( - ): mg mg mg p.o. Day 35-37: ( - ): mg mg mg p.o.



ALL IC-BFM 2002 Appendix 3.0.b 1/2+2/2

Protocol I/I'/Phase 2 Name: Weight: kg Height: cm BSA: m2 DOB: d/m/y 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

Fluid balance: I > O + 400 ml/m2/12h ⇒ 0.5 mg/kg (max. 20 mg) furosemide i.v.

+ ∆ fluid balance: ____________ ml/m2/12h ____________ ml/m2/12h Furosemide: ____________ mg i.v. ____________ mg i.v.

Day 38 � 41: mg Cytarabine (75 mg/m2/d) i.v.

( - )

Day 45: ( )LP mg Methotrexate IT at age-adjusted dosage (see below) Day 45 � 48: mg Cytarabine (75 mg/m2/d) i.v. ( - )

Day 52: BMP (in case of NR day 33) ( ) Day 52 � 55: mg Cytarabine (75 mg/m2/d) i.v. ( - )

Day 59: ( )LP mg Methotrexate IT at age-adjusted dosage (see below)

Day 59 � 62: mg Cytarabine (75 mg/m2/d) i.v. ( - )

Lab tests: CBC, electrolytes, creatinine, urea, G, U/S-osmolality, alb, ALT, AST, bilirubin, urinalysis





Day 36 � 63: mg 6-Mercaptopurine (60 mg/m2/d) p.o.

( - )



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ALL IC-BFM 2002 Appendix 3.0.c 1.1 Protocol mM

SR BCP-ALL IR BCP-ALL

1. MTX 2. MTX 3.MTX 4. MTX

Name: Weight: kg Height: cm BSA: m2

DOB: d/m/y CLcr: ml/min/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) mg Methotrexate (2,000 mg/m2/d) p.i. (24 h) urine pH ≥ 7 mg Methotrexate (1/10) loading dose p.i. (30 min)

mg Methotrexate (9/10) p.i. (23.5 h)

ml G 5% / NaCl 0.45% aa (3,000 ml/m2/24h) ml/h + mmol NaHCO3 (180 mmol/m2/24h) + ml KCl 7.45% (90 ml/m2/24h)

Day 1 (1500) LP: mg MTX IT Dosage: <1 1 2 ≥ 3 Age (yr) 6 8 10 12 mg MTX IT

Day 2 + 3 + post - MTX hydration:

ml G 5% / NaCl 0.45% aa (3,000 ml/m2/24h) + mmol NaHCO3 (180 mmol/ m2/24h) + ml KCl 7.45% (90 ml/m2/24h)

Day 2 + 3 + Leucovorin rescue:

mg LCV (15 mg/m2/SD) i.v. at: _______42 h, _______48 h, _______54 h

Day 1 � 3 - mg 6-Mercaptopurine (25 mg/m2/d) p.o. in evening on empty stomach w/o milk

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 Fluid balance: If I > O + 400 ml/m2/12h ⇒ 0.5 mg/kg (max. 20 mg) furosemide i.v.

+ ∆ fluid balance: _____ _____ _____ _____ _____ ml/m2/12h Furosemide: _____ _____ _____ _____ _____ mg i.v.

Supportive: Drug Date 1. _____________________ 2. _____________________ 3. _____________________ 4. _____________________

Date:________ Signature: Physician 1_______________ Physician 2 _______________

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ALL IC-BFM 2002 Appendix 3.0.c 2.1 Protocol M

1. MTX 2. MTX 3.MTX 4. MTX


DOB: d/m/y CLcr: ml/min/m2 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:


Day 1 (1400) mg Methotrexate (5,000 mg/m2/d) p.i. (24 h) urine pH ≥ 7 mg Methotrexate (1/10) loading dose p.i. (30 min)



Day 1 (1500) LP: mg MTX IT Dosage: <1 1 2 ≥ 3 Age (yr) 6 8 10 12 mg MTX IT

Day 2 + 3 + post - MTX hydration:



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 - mg 6-Mercaptopurine (25 mg/m2/d) p.o. in evening on empty stomach w/o milk

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 Fluid balance: If I > O + 400 ml/m2/12h ⇒ 0.5 mg/kg (max. 20 mg) furosemide i.v.

+ ∆ fluid balance: _____ _____ _____ _____ _____ ml/m2/12h Furosemide: _____ _____ _____ _____ _____ mg i.v.

Supportive: Drug Date 1. _____________________ 2. _____________________ 3. _____________________ 4. _____________________

Date:________ Signature: Physician 1_______________ Physician 2 _______________

ALL

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Dos

e m

odifi

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tic a

gent

s ad

ded

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mitt

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YE

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NO

Des

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tion

of m

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n(s)

and

reas

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in a

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ALL IC-BFM 2002 Appendix 3.0.d 1 Protocol II/Phase 1

SR-1 IR-1 HR-2A 1. 2. HR-2B

Name: Weight: kg Height: cm BSA: m2 DOB: d/m/y Start: ___/___/___ End: ___/___ /___ Day 1: ( ) Diagnostics: BMP (optional)

LP ( if CNS � 3 status ) 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%



Day 18: U L-Asparaginase (E. coli, native, Fa. Medac) (10,000 U/m2/d) p.i. over 1h ( ) in 50 ml NaCl 0.9% LP ( if CNS � 3 status ) mg Methotrexate IT at age-adjusted dosage (see below)

Day 22: 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%

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%

Day 1 � 21: mg Dexamethasone (10 mg/m2/d) p.o./i.v. ( - ) mg mg mg p.o./i.v. Dexamethasone � taper: Day 22-24: ( - ): mg mg mg p.o./i.v. Day 25-27: ( - ): mg mg mg p.o./i.v. Day 28-30: ( - ): mg mg mg p.o./i.v.


Cave: Allergic reactions to L-ASP are frequent at this stage of treatment. See text for

alternative therapy.

Supportive 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: Weight: kg Height: cm BSA: m2 DOB: d/m/y Start: ___/___/___ End: ___/___ /___ Lab tests: CBC, electrolytes, creatinine, urea, G, U/S-osmolality, alb, ALT, AST, bilirubin, urinalysis









Day 36 � 49: mg 6-Thioguanine (60 mg/m2/d) p.o.

( - )




ALL

IC-B

FM 2

002

Ap

pend

ix 3

.0.e

CPM

p .i.

(1h)

5

00 m

g/m

2 /d =

(+

MES

NA:

200

mg/

m2i.v

. x3

at 0

, 4, 8

h)

ARA -

C i.v

.

75

mg/

m2 /d

=

6-TG

p .o .

(14

d) 6

0 m

g/m

2 /d =

L-AS

P p

.i. (1

h) 1

0,00

0 U

/m 2 /d

=

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oli-

MED

AC/K

YOW

A)

DEX

A p

.o ./i

.v .

10 m

g/m

2 /d =

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i .v.

1.5

mg/

m2 /d =

(m

axim

um: 2

.0 m

g/SD

)

DO

X p .

i . (1

h)

30

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m2 /d

=

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Day

18

1522

29

()*

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I.T

.

=

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ose

age

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pted

: <1

1

2

≥ 3

Y

M

T XIT

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8

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f CN

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.

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cm

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m2

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t Pha

se 2

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. m

g

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Start of 6- MP/MTX:

DO

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e:

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ter:

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nial

radi

othe

rapy

:

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Yes

, fro

m

till

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l dos

e:

.

G

y

Frac

tions

(n):

Send

cop

y on

com

plet

ion

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atio

nal s

tudy

coo

rdin

ator

Si

gnat

ure

Fi

ll in

add

ition

al to

xici

ty fo

rms f

or P

hase

1 &

2 !

Dos

e m

odifi

catio

n?

Cyt

osta

tic a

gent

s ad

ded

or o

mitt

ed?

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S �

NO

Des

cri p

tion

of m

odifi

catio

n(s)

& re

ason

(s):

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: Weight: kg Height: cm BSA: m2 DOB: d/m/y Start: ___/___/___ End: ___/___ /___ Day 1: 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% Diagnostics: BMP (optional)

LP ( if CNS � 3 status ) mg Methotrexate IT at age-adjusted dosage (see below)




Day 1 � 14: mg Dexamethasone (10 mg/m2/d) p.o./i.v. ( - ) mg mg mg p.o./i.v. Dexamethasone � taper: Day 15-17: ( - ): mg mg mg p.o./i.v Day 18-20: ( - ): mg mg mg p.o./i.v. Day 21-23: ( - ): mg mg mg p.o./i.v.


Cave: Allergic reactions to L-ASP are frequent at this stage of treatment. See text for

alternative therapy.



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: Weight: kg Height: cm BSA: m2 DOB: d/m/y Start: ___/___/___ End: ___/___ /___ 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



+ ∆ fluid balance: ____________ ml/m2/12h Furosemide: ____________ mg i.v.





Day 15 � 28: mg 6-Thioguanine (60 mg/m2/d) p.o.

( - )




ALL

IC-B

FM 2

002

Appe

ndix

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.

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rm:

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cue

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h)

Day

1

2

3

4

5

6

11

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ght =

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ght

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=

kg

cm

m2

DO

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mg/

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SD m

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d

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e

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nt in

rem

issi

on ?

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es

No

M

TX (

µ mol

/l)

CF -

Res

cue

24

h

36 h

42

h

48 h

54

h

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ter:

(mg)

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No

until

hou

r

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nded

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ll in

add

ition

al

to

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ty fo

rm !

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catio

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mitt

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NO

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escr

iptio

n of

mod

ifica

tion(

s) &

reas

on(s

):

Send

cop

y on

com

plet

ion

to n

atio

nal s

tudy

coo

rdin

ator

(

q 12

h)

ALL IC-BFM 2002 Appendix 3.0.f 1 BLOCK HR � 1' Name: Weight: kg Height: cm BSA: m2

DOB: d/m/y CLcr: ml/min/m2 Start: / / 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 - mg Dexamethasone p.o./i.v. (20 mg/m2/d): mg, mg, mg



Day 1 + mg Vincristine (1.5 mg/m2/d) slowly i.v. (max. 2.0 mg/SD), at least 1h before MTX Day 1 (1400) mg Methotrexate (5,000 mg/m2/d) p.i. (24 h)

urine pH ≥ 7 mg Methotrexate (1/10) loading dose p.i. (30 min)


ml G 5% / NaCl 0.45% aa (3,000 ml/m2/24) ml/h + mmol NaHCO3 (180 mmol/m2/24h) + ml KCl 7.45% (90 ml/m2/24h)

Day 1 (1500) LP: mg MTX IT, mg ARA-C IT, mg Prednisone IT

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 Day 2 + 3 + post - MTX hydration:



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

Day 4 - 6 - INFUSION ml G 5% / NaCl 0.45% aa (3,000 ml/m2/24h) +

ml KCl 7.45% (90 ml/m2/24h)

Day 5 mg Cytarabine (2,000 mg/m2/SD) in 250 ml G 5%, p.i. (3 h) 900 + 2100 2 doses 12 h apart (900 + 2100); close monitoring; Cave: ataxia, nystagmus Day 5 � 8 - Dexamethasone eye drops: tid; B6: 150 mg/m2 i.v./p.o. q 12h for 2 � 3 days

Day 6 + mg Vincristine (1.5 mg/m2/d) slowly i.v. (max. 2.0 mg/SD), 10 � 12h before L-ASP Day 6 + ___________ U E. coli L-asparaginase (25,000 U/m2/d) in 250 ml NaCl 0.9%, p.i. (2 h) Day 11 ___________ U E. coli L-asparaginase (25,000 U/m2/d) in 250 ml NaCl 0.9%, p.i. (2 h)

Day 11 + µg G-CSF (5 µg/kg/d s.c.) until ANC > 5,000/µL

Fluid balance: q 12h, if I > O + 400 ml/m2 /12h ⇒ mg furosemide i.v. (0.5 mg/kg/SD, max. 20 mg)

Date: Supportive therapy: HT3 blocker & other indispensable medications pro re nata Signature: Physician 1 Physician 2

ALL

IC-B

FM 2

002

A

ppen

dix

3.0.

g

DEX

Ap.

o /i.

v.

.

20m

g/m

2 /d

=

VDS

i.v

.

3

mg/

m2 /d

=

(max

imum

: 5.0

mg/

SD)

DNR

p.i.

(24h

) 3

0 m

g/m

2

=

HD M

TXp.

i. (2

4h)

5,00

0 m

g/m

2 =

IFO

p.i.

(1h)

800

mg/

m2

x 5=

(+ M

ESN

A: 3

00 m

g/m2

i.v. x

3 at

0, 4

, 8h)

L-AS

P p

.i.(2

h)25

, 000

U/m

2 /d =

(E.c

oli- M

EDAC

/KYO

WA )

*

CF-

Res

cue

i.v.

1

5 m

g/m

2

=

x3 (h

: 42,

48,5

4)

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nly

in C

NS-

posi

tive

pts

Day

1

2

3

4

5

6

11

BM

W

eigh

t =

Hei

ght

=

BSA

=

kg cm m2

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.=

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/

mg

dose

by

age

12

30

1

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10

2

6

8 m

g

=>

2 <

3 Y

1h

afte

r sta

rt H

DM

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8

2

0 6

mg

=

> 1

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Y

6

16

4

mg

< 1

Y

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e

DO

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Nam

e:

D

ata

befo

re s

tart

of b

lock

: Pa

tient

in re

mis

sion

?

Y

es

N

o

.

U

mg/

SD

mg/

SD

mg

mg/

d .

mg/

SD

mg/

SD

.

Cen

ter:

AL

LIC

- BFM

200

2 : B

lock

HR

- 2 �

1.

2

.

HR

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lock

T

hera

py a

rm:

H

R -

1

H

R- 2

A

H

R -

2B

M

TX (

µ mol

/l)

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cue

24

h

36 h

42

h

48 h

54

h

(mg)

Yes

No

until

hou

r

Exte

nded

Res

cue

Fill

in a

dditi

onal

toxi

city

form

!

Si

gnat

ure

Send

cop

y on

com

plet

ion

to n

atio

nal s

tudy

coo

rdin

ato r

Dos

e m

odifi

catio

n?

Cyt

osta

tic a

gent

s ad

ded

or o

mitt

ed?

Y

ES �

NO

D

escr

iptio

n of

mod

ifica

tion(

s) &

reas

on(s

):

ALL IC-BFM 2002 Appendix 3.0.g 1 BLOCK HR � 2'


DOB: d/m/y CLcr: ml/min/m2 Start: / / 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




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 + mg Vindesine (3 mg/m2/d) slowly i.v. (max. 5.0 mg/SD), at least 1 h before MTX Day 1 (1400) mg Methotrexate (5,000 mg/m2/d) p.i. (24 h) urine pH ≥ 7 mg Methotrexate (1/10) loading dose p.i. (30 min)



Day 1 (1500) LP: mg MTX IT, mg ARA-C IT, mg Prednisone IT +Day 5: CNS + ditto ditto 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 Fluid balance: q 12h, if I > O + 400 ml/m2 /12h ⇒ mg furosemide i.v. (0.5 mg/kg/SD, max. 20 mg) Day 2 + 3 + post - MTX hydration:

ml G 5% / NaCl 0,45% aa (3,000 ml/m2/24h) + mmol NaHCO3 (180 mmol/ m2/24h) + ml KCl 7.45% (90 ml/m2/24h)

Day 2 + 3 + Leucovorin rescue: 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 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 Day 4 - 6 - INFUSION: ml G 5% / NaCl 0.45% aa (3,000 ml/m2/24h) + ml KCl 7.45% (90 ml/m2/24h) Day 1 - 6 - Fluid balance: q 12 h

If I > O + 400 ml/m2 /12h ⇒ mg furosemide i.v. (0.5 mg/kg/SD, max. 20 mg)

Day 5 mg Daunorubicin (30 mg/m2/SD) in ml NaCl 0.9%, p.i. (24 h) Day 6 + mg Vindesine (3 mg/m2/d) slowly i.v. (max. 5.0 mg/SD), 10 � 12 h before L-ASP Day 6 + U E. coli L-asparaginase (25,000 U/m2/d) in 250 ml NaCl 0.9%, p.i. (2 h) Day 11 U E. coli L-asparaginase (25,000 U/m2/d) in 250 ml NaCl 0.9%, p.i. (2 h) Day 11 + µg G-CSF (5 µg/kg/d s.c.) until ANC > 5,000/µL

Date: Supportive therapy: HT3 blocker & other indispensable medications pro re nata Signature: Physician 1 Physician 2

A

LL IC

-BFM

200

2

App

endi

x 3.

0.h

DEX

A p.

o./i.

v.

20m

g/m

2 /d =

VP - 1

6 p.

i.(1

h)

100

mg/

m2

x5 =

(q

12

h)

Day

1

2

3

4

5

6

1

1

L-AS

P p

.i.(2

h)

25, 0

00 U

/m2 /d

=

(E.c

oli-

MED

AC/K

YOW

A)

HD

ARA-

Cp.

i. (3

h)2,

000

mg/

m2

x4 =

(q

12

h)

DO

B:

Nam

e:

Cen

ter:

W

eigh

t =

Hei

ght

=

BSA

=

kg

cm m2

MTX

/AR

A-C

/PR

EDI.T

. =

/

/

m

g

dos

e by

age

12

30

1

0m

g =>

3 Y

10

26

8

mg

=

> 2

< 3

Y 8

20

6

mg

=

> 1

< 2

Y 6

16

4 m

g

<

1 Y

Dat

e

D

ata

befo

re s

tart

of b

lock

: Pa

tient

in re

mis

sion

?

Y

es

N

o

U

mg/

SD

mg /

SD

. m

g/d

AL

L IC

- BFM

200

2 : B

lock

HR

- 3 �

1.

2

.

HR

- 3'

blo

ck

The

rapy

arm

:

H

R -

1

H

R -

2A

H

R- 2

B

Fill

in a

dditi

onal

toxi

city

form

!

Si

gnat

ure

Send

cop

y on

com

plet

ion

to n

atio

nal s

tudy

coo

rdin

ator

Dos

e m

odifi

catio

n?

Cyt

osta

tic a

gent

s ad

ded

or o

mitt

ed?

YE

S �

NO

Des

cri p

tion

of m

odifi

catio

n(s)

& re

ason

(s):

ALL IC-BFM 2002 Appendix 3.0.h 1 BLOCK HR � 3'


DOB: d/m/y CLcr: ml/min/m2 Start: / / 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



Day 1 � 2 - mg Cytarabine (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 -

Day 1 - 6 - INFUSION

ml G 5% / NaCl 0.45% aa (3,000 ml/m2/24h) + ml KCl 7.45% (90 ml/m2/24h)

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 LP: mg MTX IT, mg ARA-C IT, mg Prednisone IT

Day 6 + U E. coli L-asparaginase (25,000 U/m2/d) in 250 ml NaCl 0.9%, p.i. (2 h) Day 11 U E. coli L-asparaginase (25,000 U/m2/d) in 250 ml NaCl 0.9%, p.i. (2 h)

Day 11 + µg G-CSF (5 µg/kg/d s.c.) until ANC > 5,000/µL

Day 1 - 6 - Fluid balance: I > O + 400 ml/m2/12h ⇒ 0.5 mg/kg (max. 20 mg) furosemide i.v.

+ ∆ fluid balance: _____ _____ _____ _____ _____ _____ _____ _____ _____ ml/m2/12h Furosemide: _____ _____ _____ _____ _____ _____ _____ _____ _____ mg i.v.

Date: ________ Supportive: Drug Date Signature: Physician 1_______________ Physician 2 _______________ 1. _______________________

2. _______________________ 3. _______________________ 4. _______________________

A

LL IC

-BFM

200

2

App

endi

x 3.

0.i

MTX

p.o

. 20

mg/

m 2 /w

k

6-M

P p.

o. 5

0 m

g/m

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(day

: 1 �

70)

Wee

k 1

2 3

4 5

6 7

8 9

10

Dat

e

MTX

mg/

wk

6-M

P m

g/d

WBC

/ µL

Hg

g/

dL

* Blo

od c

hem

istr

y:

PLT

/µL

ALT

U

/LAS

T

U/L

i.v. A

TB

Bili

µm

ol/L

(n d

ays)

AL

P

U/L

R

BC tr

ansf

.(n)

Cre

a µ

mol

/L

PL

T tra

nsf.

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ture

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k)

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cros

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Leucovorin � Rescue Plan

Principles: • Immediate MTX24 / 42 / 48 level measurement.

Table 1: Regular Plasma MTX Levels & Standard LCV Rescue MTXhour µmol/L Rescue at: [h] Leucovorin i.v. [mg/m2] MTX24 < 150 MTX36 < 3.0 MTX42 ≤ 1.0 42 15

MTX48 ≤ 0.4 48 15

54 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 µmol/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).

Table 2: LCV Rescue in Case of Disproportionately High Plasma MTX Levels • MTX42 1 to < 5.0 µmol/L or • MTX48 > 0.4 µmol/L

• LCV i.v. q 6 h until MTX ≤ 0.25 µmol/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 µmol/L See section 2.2.3.2 (p 58) & section 3.10 (p 135)

• LCV i.v. q 6 h until MTX ≤ 5.0 µmol/L • Dosage: LCV [mg] = MTX [µmol/L] x weight [kg], 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 [µmol/L] 5

75 mg / m2

4 60 mg / m2

3 45 mg / m2

2 30 mg / m2

1 15 mg / m2

0.25

NO RESCUE

0 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 1 2 2A 2B

Acute Toxicity During / After ALL IC- BFM 2002 Protocol I: Phase 1 Phase 2 Protocol I': Phase 1 Phase 2

Protocol mM: 1.MTX 2.MTX 3.MTX 4.MTX Protocol M: 1.MTX 2.MTX 3.MTX 4.MTX

1. 2. HR-1' Block 1. 2. HR-2' Block 1. 2. HR-3' Block

1. 2. Protocol II: Phase 1 Phase 2 1. 2. 3. Protocol III: Phase 1 Phase 2

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 0 1 2 3 4 General condition

normal activity

mild impairment

age-related activities strongly limited

bedridden, in need for nursing

intensive care, very sick

Infection Infection none mild pathogen not identified,

IV antibiotics pathogen identified

IV antibiotics septic shock

Fever (°C) < 38 38 � 39 > 39 � 40 > 40 < 24 h > 40 ≥ 24 h Gastrointestinal toxicity Nausea none adequate food

intake markedly decreased food

intake almost no food

intake TPN necessary

Vomiting (in 24 h) 0 1 2 � 5 6 - 10 > 10/TPN necessary Stomatitis none painless ulceration,

erythema painful ulceration, can still

eat painful ulceration,

cannot eat TPN required due to

stomatitis Diarrhea (stool frequency/day)

none 2 - 3 4 � 6 or night stools or light cramps

7 � 9 or incontinence or strong cramps

? 10 or bloody diarrhea or TPN required

Liver toxicity S- bilirubin normal for age > N � 1.5 x N > 1.5 � 3.0 x N > 3.0 � 10.0 x N > 10.0 x N S- ALT/ S- AST normal for age > N � 2.5 x N > 2.5 � 5.0 x N > 5.0 � 20.0 x N > 20.0 x N Renal toxicity: Creatinine normal for age > N � 1.5 x N > 1.5 � 3.0 x N > 3.0 � 6.0 x N > 6.0 x N Proteinuria (g/L) none < 3.0 3.0 � 10.0 > 10.0 nephrotic syndrome Hematuria none microscopic macroscopic w/o clots macroscopic with clots transfusion required Creatinine clearance (ml/min/1,73m2)

≥ 90 60 - 89 40 � 59 20 - 39 ≤ 19

Cardiac toxicity Arrhythmia none asymptomatic,

no therapy recurrent / persistent,

no therapy therapy required hypotension, ventr.

arrhyth., defibrillation Cardiac function normal for age EF ↓ < 20% from

baseline value EF ↓ ≥ 20% from

baseline value mild cardiac insuff.,

therapeutically compensated

severe / refractory cardiac insufficiency

Echo-CG: LVSF ≥ 30% ≥ 24% - < 30% ≥ 20% - < 24% > 15% - < 20% ≤ 15% Neurologic toxicity Central neurotoxicity none transient lethargy somnolence < 50% of the

day, moderate disorientation

somnolence ≥ 50% of the day,

disorientation, hallucinations

coma, seizures

Peripheral neurotoxicity, Myopathy

none paresthesias and/or decreased tendon

reflexes

severe paresthesias and/or mild weakness

unbearable paresthesias,

marked motor deficits

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

Other toxicity: _______________________________________________________________________________________________ Abbreviations: N normal for age Stamp: EF ejection fraction LVSF left-ventricle shortening fraction Date: _____/_____/_____ d/m/y Signature: _____________ Please send copy to National Study Coordinator & National Data Manager

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)

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 µmol/L (< 1 mg/dL). N = ULN = Upper Limit of Normal = 17 µmol/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

[µmol/L] (mg/dL) Newborn < 106 < 1.2 Till end of 5th yr < 44 < 0.5 Till end of 10th yr < 88 < 1.0 > 10 yr < 106 < 1.2

N = ULN = Upper Limit of Normal 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: K1 x Height [cm] K2 x Height [cm]

CLcr [ml/min/1.73 m2] = = Plasma Creatinine [mg/dL] Plasma Creatinine [µmol/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 Isolated remarkable ECG findings not requiring therapy, e.g. extrasystoles Grade 2 Recurrent remarkable ECG findings not requiring therapy, e.g. repetitive

premature systoles Grade 3 Serious arrhythmia necessitating therapy, e.g. atrial fibrillation or flatter Grade 4 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 EF decreased by < 20% from pre-treatment value Grade 2 EF decreased by > 20% from pre-treatment value Grade 3 Cardiac insufficiency requiring therapy and responding to it Grade 4 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.


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___.___.___ After End Of Treatment End of

Treatment (Maintenance)

1. yr 20__

2. yr 20__

3. yr 20__

4. yr 20__

5. yr 20__

- 10. yr -20__

Diagnostics to rule out recurrence Complete physical exam.+ testicles

x monthly q 3 months q 3 months q 4 months q 6 months x

Neurology x monthly q 3 months q 3 months q 4 months q 6 months x CBC + diff. LDH

x monthly q 3 months q 3 months q 4 months q 6 months x

FU & late-effects diagnostics Blood chemistry1 x x Renal function2 x q 4 months q 6 months Viral serology3 x x Ab titers4 x x Endocrinology Percentiles5 x x x x x x x Tanner / breast abnorm. / volume of testicles

x q 6 months q 6 months x x x x

Serum parameters6 in case of remarkable deviations in pubertal development Spermiogram once after 18. yr Ophthalmology x x US � thyroid fT3, fT4, TSH7

x x x

ECG/ (stress)-Echo-CG x q 2 yr BMD x x Neuropsychologic tests (motor, coordination, cognitive domain): from 6. yr of age

x

FU after radiotherapy 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 CRP, ESR, bilirubin, AST, ALT, γ-GT, ALP, LDH, α-amylase, ferritin, immunoglobulins 2 Blood: phosphate, calcium, magnesium, sodium, potassium, creatinine, bicarbonate

Urine: urinalysis, phosphate, calcium, creatinine

3 HBV, HCV, CMV, HIV 4 Diphtheria, tetanus 5 X-ray of left hand/wrist (bone age) 6 LH, FSH, Prolactin, Estradiol, (stimulation tests, if need be) 7 Only after cranial radiotherapy

APPENDIX 4

4.0 IMMUNOPHENOTYPIC CLASSIFICATION OF

ACUTE LEUKEMIAS


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 Definition Typical findings

proB ALL CD10neg CD20neg c ALL CD10pos intraIgMneg B

precursor preB ALL intraIgMpos CD10pos

B precursor (shared features)

• 2 or 3 of: CD19pos, (intra)CD79apos, CD22pos

• CD3neg, intraCD3neg, κneg and λneg

HLADRpos, intraTdTpos, CD7neg

mature B either κpos or λpos aberrant My Agsneg,

CD20pos, intraTdTneg, 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 κ and λ usually indicates improper handling of the specimen, mostly low transport temperature.

• Intracellular κ or λ 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

intermediate T ALL CD1apos CD4pos & CD8pos,

[Some cases may be CD3pos ]

mature T ALL CD3pos CD1aneg TCRαβpos T ALL TCRαβpos

T lineage

TCRγδpos T ALL TCRγδpos T lineage (shared features)

(intra)CD3pos , CD7pos

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 points

B lineage T lineage My lineage

2 (intra)CD79a, intraIgM, (intra)CD22

(intra)CD3, TCRαβ, TCRγδ intraMPO

1 CD19, CD10, CD20 CD2, CD5, CD8, CD10 CD13, CD33, CD65, CD1170.5 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 mini-mini 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 Leukämien (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 ([email protected]).

APPENDIX 5

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All Ic Append

Documents

national groupcenter

similar baseline

general principles

national reference

acute lymphoblastic

central nervous

bone marrow

national data