Eortc 2010

CLG Treatment guidelines for
Acute Lymphoblastic Leukemia

Therapeutic regimens, Dose modifications and Toxicities
(to be used in paralel with the EORTC 58081 study)
• First Version – agreed after Ghent – 24/08/2010 – named :

CLG_ALLFrontline_Treatmentguidelines_vs02
• Second Version – agreed after Toulouse – 23/11/2010 – named :
CLG_ALLFrontline_Treatmentguidelines_vs03.02
1 RISK GROUP DEFINITIONS........................................................................................5
2 GENERAL SCHEME OF THE TREATMENT

GUIDELINES ....................................................................................................................................................8
3 IMPORTANT “MINOR” ADAPTATIONS AND

CHANGES IN COMPARISON WITH THE STUDY 58951 .......9
4 VERY LOW RISK (VLR) ....................................................................................................10

4.1 Prephase VLR ........................................................................................................................................................................... 10
4.2 Protocol I A Reduced (Induction) - VLR ................................................................................................................................ 10
4.3 Protocol I B Reduced (Consolidation) - VLR ......................................................................................................................... 11
4.4 Interval therapy - VLR............................................................................................................................................................. 12
4.5 Protocol II Reduced – VLR (Reinduction or Late intensification) ....................................................................................... 13
4.6 Maintenance therapy - VLR .................................................................................................................................................... 13
5 AVERAGE RISK 1 (AR1) .................................................................................................14

5.1 Prephase - AR1.......................................................................................................................................................................... 14
5.2 Protocol I A (Induction) – AR1................................................................................................................................................ 14
5.3 Protocol I B (Consolidation) – AR1 ......................................................................................................................................... 15
5.4 Interval therapy – AR1............................................................................................................................................................. 16
5.5 Protocol II – AR1 (Reinduction or Late Intensification) ..................................................................................................... 17
5.6 Maintenance therapy – AR1 .................................................................................................................................................... 18
CLG_ALLFrontline_TreatmentGuidelines_vs03.02 data 21/11/2010 -1-

6 AVERAGE RISK 2 (AR2) - B-CELL ALL ................................................19
6.1 Prephase – AR2-B ..................................................................................................................................................................... 19
6.2 Protocol I A Augmented – AR2-B (Induction) ...................................................................................................................... 20
6.3 Protocol I B – AR2-B (Consolidation) ................................................................................................................................... 21
6.4 Interval therapy – AR2-B......................................................................................................................................................... 21
6.5 Protocol II - – AR2-B (Reinduction or Late intensification) ................................................................................................ 22
6.6 Maintenance therapy – AR2-B ............................................................................................................................................... 23
7 AVERAGE RISK 2 (AR2) - T-CELL ALL.................................................24

7.1 Prephase – AR2-T ..................................................................................................................................................................... 24
7.2 Procotol I A - AR2-T (Induction) .......................................................................................................................................... 25
7.3 Protocol I B - AR2-T (Consolidation)..................................................................................................................................... 25
7.4 Interval therapy - AR2-T......................................................................................................................................................... 26
7.5 Protocol II - AR2-T (Reinduction or Late intensification) ................................................................................................... 27
7.6 Maintenance therapy - AR2-T ................................................................................................................................................ 28
8 VERY HIGH RISK (VHR) ..................................................................................................29

8.1 Prephase – VHR ........................................................................................................................................................................ 29
8.2 Protocol I A – VHR (Induction).............................................................................................................................................. 30
8.3 Treatment of VHR patients beyond protocol IA.................................................................................................................... 30
8.4 Protocol I B augmented – VHR (1° Consolidation)............................................................................................................ 31
8.5 Protocol VANDA – VHR (2° Consolidation) ........................................................................................................................ 32
8.6 1° Interval therapy– VHR : 3 cures of HDMTX ................................................................................................................... 32
8.7 Protocol II modified – VHR ( 1° Reinduction or 1° Late Intensification).......................................................................... 33
8.8 2° Interval therapy – VHR: 3 cures of HDMTX ................................................................................................................. 34
8.9 Protocol II modified – VHR ( 2° Reinduction or 2° Late Intensification)............................................................................ 34
8.10 Maintenance therapy – VHR ................................................................................................................................................... 34
9 PRACTICAL GUIDELINES ...........................................................................................35

9.1 Prephase..................................................................................................................................................................................... 35
9.2 Induction (IA reduced, IA, IA augmented)............................................................................................................................. 35
9.3 Consolidation (IB reduced and IB).......................................................................................................................................... 37

9.4 1° Consolidation for VHR ( IB augmented)............................................................................................................................ 37
9.5 Interval therapy ........................................................................................................................................................................ 37
9.6 Reinduction or Late Intensification (II reduced, II normal, II modified) ............................................................................ 39
9.7 2° Consolidation VHR ( VANDA) ........................................................................................................................................... 39
9.8 Maintenance .............................................................................................................................................................................. 40
10 GENERAL DRUG INFORMATION ................................................................42

10.1 Adriamycin (= Doxorubicin) (ADR)........................................................................................................................................ 42
10.2 Asparaginase (L-A’ase) ............................................................................................................................................................ 42
10.3 Cyclophosphamide (CPM) ....................................................................................................................................................... 42
10.4 Cytosine-arabinoside (ARA-C) ................................................................................................................................................ 43
10.5 Daunorubicin (DNR)................................................................................................................................................................. 43
10.6 Etoposide (VP-16) ..................................................................................................................................................................... 43
10.7 Corticosteroids .......................................................................................................................................................................... 43
10.8 Methotrexate (MTX)................................................................................................................................................................. 43
10.9 6-mercaptopurine (6-MP)......................................................................................................................................................... 43
10.10 6-thioguanine (6-TG) ............................................................................................................................................................ 43
10.11 Vincristine (VCR) ................................................................................................................................................................. 44
10.12 Vindesine (VDS) .................................................................................................................................................................... 44
11 DEFINITIONS AND TREATMENT OF INITIAL EXTRA-

MEDULLARY INVOLVEMENT ..........................................................................................45
11.1 Initial CNS status (CSF findings at Day 1) ............................................................................................................................. 45
11.2 “Late”CNS status (beyond the 1° IT injection) ..................................................................................................................... 45
11.3 CNS involvement at diagnosis: ................................................................................................................................................ 46
11.4 Treatment of CNS involvement ............................................................................................................................................... 47
11.5 Cytocentrifugation technique (cytospin) and instructions for cerebro-spinal fluid (CSF)................................................. 49
11.6 Gonadal involvement:............................................................................................................................................................... 50
12 MRD GUIDELINES .................................................................................................................51

12.1 When MRD measurements? .................................................................................................................................................... 51
12.2 Decisions taken from MRD results:......................................................................................................................................... 51

12.3 Schematic overview................................................................................................................................................................... 52
13 SCT INDICATIONS ................................................................................................................53

13.1 Patient Selection for SCT ......................................................................................................................................................... 53
13.2 Timing of SCT:.......................................................................................................................................................................... 53
13.3 Schematic Overview.................................................................................................................................................................. 54

1 Risk Group Definitions
These Risk Group definitions are a copy of the Risk Group definitions used
in the EORTC Study 58081
Note: for bilineage l ALL, the risk group is determined by the most prominent immunosubtype. If B
predominant: AR1, AR2 (B) or VHR following the other criteria. If T predominant: AR2 (T) or VHR.
1 Very low risk (VLR)

Acute lymphoblastic leukaemia with the following diagnostic criteria:
B-cell lineage with a leukocyte count < 10x109/l

♦ and age > 1 year and < 10 years
♦ and absence of CNS involvement with a CNS 1 status of the CSF
♦ and absence of gonadal involvement
♦ and absence of t(9;22)/BCR-ABL, of t(4;11)/MLL-AF4, of 11q23/MLL rearrangement
and DNA index (DI) ≥1.16 and < 1.50, and chromosome number 54-66 or DI ≥1.16 and
< 1.50, and chromosome number is unknown or chromosome number 54-66, and D. I. is not
assessed
NB: all criteria are required.
♦ In the absence of DI and of cytogenetics results, patients meeting all other VLR criteria
will be treated according to AR 1 group (see below).
♦ A normal karyotype (46 chromosomes without any structural abnormality) can only be
ascertained when at least 20 mitoses have been analyzed. When the number of normal interpretable
mitoses < 20, the result is to be labeled “technical failure” and should be ignored for patient
stratification. For instance, a patient with a leukemic clone with a DI >or= 1.16 and a normal karyotype
on less than 20 mitoses may be allocated to the VLR group (if all other VLR criteria are met).
♦ If both DI and cytogenetics are available but are discordant, the data must be compared in
order to rule out a non-informative result. If karyotype presents 51 to 66 chromosomes whereas the
DNA index is close to 1 (0.97-1.03), take only into account the result of karyotype (because DNA index
failed to detect aneuploidy, and only detected nonleukemic cells). If karyotype is normal whereas DNA
index detects aneuploidy (DI) > or = 1.16 and < 1.50), take into account only the result of DNA index
(because karyotype failed to detect aneuploidy and detected only non leukemic cells). In this case, it is
recommended to confirm chromosome gains using interphasic FISH with at least 4 probes of the
following chromosomes X,4,6,10,14,17,18,21.
♦ If both DI and cytogenetics are available but are discordant, the most biologic acceptable
of the two factors must be taken into account if DI≥1.16 and <1.50, and chromosome number is 51,52 or
53; If any problem where the karyotype is confusing, please contact the cytogenetic coordinator
♦ If DI > or = 1.16 and < 1.50 whereas karyotype is abnormal with chromosome number ≤
50 (which is very unlikely), the patient cannot be allocated to the VLR group either.

♦ When two (or more) leukemic clones are present and different with respect to DI or
cytogenetics (this type of bi- or multiclonality is mostly revealed by the presence of two or more peaks
on DI evaluation), the most unfavorable should be taken into consideration for patient stratification,
even when the clone with the lowest DI or the lowest chromosome number is quantitatively the smallest.
Ex: 2 clones on DI: one hypo (DI ≥ 0.7 and ≤ 0.8) and one hyper (DI ≥ 1.4 and ≤ 1.8), and karyotype
shows only a hyperdiploid clone, the patient cannot be allocated to the VLR group but must go to the
VHR group. The profile of chromosome gains specific of near-triploidy/duplication hypo must be
ascertained by the central reviewer of cytogenetic analyses.
AND with the following response criterion:
Good response to the prephase (GPhR)
2 Average risk (AR)

ALL with good response to the prephase who are neither VLR nor VHR.
AR patients are sub-stratified in:
Avereage Low Risk or AR 1 :

♦ B-cell lineage ALL with < 100x109/l
♦ patients with CNS1 or TLP –
♦ Very Low Risk patients (VLR in CLG) with “Late CNS1” or “TLP+Late CNS1”status
Average High Risk or AR 2

• B-cell lineage ALL with ≥ 100x109/l
♦ T-cell lineage ALL whatever the leukocyte count and without CNS involvement
♦ Very Low Risk (VLR) B-cell lineage ALL patients or Average Low Risk (AR1) Group B-cell
lineage ALL patients with CNS involvement
♦ gonadal involvement
Note: Down’s syndrome patients with AR2 features will be allocated to the AR1 group.
3 Very high risk (VHR)

Acute lymphoblastic leukaemia with one of the following diagnostic criteria:
• t(9;22) or bcr/abl *
• OR t(4;11) / MLL-AF4
• OR 11q23 / MLL rearrangement including t(9;11) /MLL-AF9, t(10;11) /MLL-AF10 and
t(6;11)/MLL-AF6 and t(11;19),/MLL-ENL. See remark below for the subgroup t(11:19)
**,
• OR near-haploidy (≤ 34 chromosomes or DI < 0.67)
OR hypodiploid (35-43 chromosomes or D. I. ≥ 0.67 and ≤ 0.94) (or near-triploidy
resenting the specific profile of near-triploidy/duplication of hypodiploid 30-40
chromosomes. This diagnosis must be confirmed by the detection of both clones on DI -
hypo DI ≥ 0.65 and ≤ 0.94 and near-triplo DI ≥ 1.3 and ≤ 1.8)
• OR iamp21
• OR Average High Risk Group (AR2) patients with CNS involvement
OR with one of the following response criteria:
• Poor response to the prephase

• OR minimal residual disease (MRD) ≥10-2 at evaluation of the induction
• OR failure to achieve CR/GPR after induction
• OR failure to achieve CR after consolidation
• OR minimal residual disease ≥10-3 at the end of IB
Note:
* Patients with t (9;22) or bcr/abl will be treated following specific therapeutic recommendations.
** Patients with T ALL and t(11:19) may have a better prognosis. This is still debated. Please contact
the clinical coordinators.
- Down’s syndrome patients with VHR features will be allocated to the AR1 group.

•
2 General Scheme of the treatment guidelines

3 Important “Minor” Adaptations and Changes in
comparison with the Study 58951
We describe here some “minor” but important changes that we introduced in the treatment in comparison with
the previous study 58951.
As you know we adapted our guidelines in the first place according to the IDMC recommendations after
closure of the 58951 but we also deduced some adaptations from the BFM 2000 results, from the CCG and the
experience from Lyon. Of course it is mandatory to read the full recommendations but this section is to remind
you some important “minor” adaptations and changes.
Prephase:
• The corticosteroid in the prephase is Prednisolone for all patients.
Inductions:
• Prednisolone is also the corticosteroid in the inductions except for :
o AR 2 – B ALL: Dexa at 6 mg/m²
o AR 2 – T ALL: Dexa at 10mg/m². The maximum dose of Dexa in induction is 15mg/day.
• In the Inductions for all (except for the AR 2- T ALL) the dose of Coli Aspa is 10.000 UI/m²
• For the induction of the AR 2 – T ALL the Coli Aspa dose has been changed in relation to the Dexa
dose of 10mg/m². The BFM used the Coli Aspa at the dose of 5.000 U/m². We prefer also the BFM dose
of 5000 UI/m² Coli Aspa.
• Leucovorin Rescue of HD MTX for AR 2 – B ALL starts at H42 and not at H36.
• The VHR risk patients will have Cyclofosfamide 1 gr IV at Day 8 of IA.
• For all CNS positive patients we have intensified the IT injections. They have more IT injections in
induction and also in Late intensification (protocol II) than in the 951 study.
Consolidations, Interval and Reinductions (Late Intensifications)
For all patients
• We have intensified the IT injections for all patients in II B. All patients will receive an second IT
during this phase.
• Leucovorin Rescue of all HD MTX starts 6 hours later at H42 (and not at H36) and at a higher dose
(15mg/m²).
• The maximum daily dose of Dexa is 15 mg in all reinductions.
For VHR Patients
• VHR: The old I B’ is replaced by an I B augmended (I B augm.)
• Also the blocks R1, R2 and R3 are not longer given.
• VANDA, double shortened Interval and double delayed intensifications (II modified) are the treatment
elements.
• For short course of Dexa (like in VANDA) the dose is NOT limited to 15 mg/day.
• In the II A modified the Doxo administrations are limited to 3 x. The dose of Doxo is also less: 25
mg/m² (instead of 4 x 30 mg in the normal II A).
Maintenance
• For all AR1 : pulses with dex/vincritine
• For AR2 – B ALL: HD MTX/aspa and also the pulses dex/vincritine but not synchrone
• For AR 2 – T ALL : HD MTX/aspa and no pulses
CNS Involvement and Treatment

• New definitions in line of international standards and also adapted treatment are proposed
• See section 11

4 Very low risk (VLR)
4.1 Prephase VLR
4.1.1 Design
Number of
Drugs Dose Route Days
days
PDN P.O.
60 mg/m²
or or 7 1 to 7
(30 mg/m² bid)
methyl-PDN I.V. (1 hour)
MTX See below * I.T. 1 1
NOTES:
* a patient with any kind of CNS disease can never be a VLR patient
Doses of MTX:
Age MTX
≥ 1 y < 2 y 8 mg
≥ 2 y < 3 y 10 mg
≥3y 12 mg
4.2 Protocol I A Reduced (Induction) - VLR

4.2.1 Design
Number
of days
60 mg/m²
PDN P.O. 21 8 to 28
(30 mg/m² bid)
1.5 mg/m²
VCR I.V. 4 8, 15, 22 and 29
(Maximum: 2.0 mg per injection)
DNR 30 mg/m² I.V. (1 h) 2* 8, 15
IT
12, 25 **
chemotherapy See below ** I.T. 2
(MTX)
12, 15, 18, 22, 25,
L-A'ase*** 10,000 U/m² I.V. (1 h) 8
29, 32 and 35
NOTES:
* VLR patients receive only 2 injections of DNR!
** Intrathecal chemotherapy (methotrexate) :
CLG_ALLFrontline_TreatmentGuidelines_vs03.02 data 21/11/2010 - 10 -

the IT is preferably not given on the same day of a vincristine injection. However if the hospital has clear and
safe procedures to prevent mistakes in delivering intrathecal medications, the dates of intrathecal injections can
be also Day 8 and Day 22
Age MTX
≥ 1 y < 2 y 8 mg
≥ 2 y < 3 y 10 mg
≥3y 12 mg
*** For adjustment of L-A’ase treatment, see 9. Practical guidelines
4.3 Protocol I B Reduced (Consolidation) - VLR

4.3.1 Conditions for starting I B (theoretically on day 36)
- Complete remission is confirmed.

- There is no VHR feature.
- PMN at least above 0,5 x 109/l and platelets > 100x109/l and blood values are increasing.
4.3.2 Design
Drugs Dose Route Number of days Days

6-MP 60 mg/m² P.O. 28 36 to 63
38 to 41,
45 to 48,
Ara-C 75 mg/m² I.V. 16
52 to 55,
59 to 62
I.T. chemotherapy
See below * I.T. 2 38, 52
(MTX)
NOTES:
* VLR patients receive no cyclophosphamide!
* Intrathecal chemotherapy (methotrexate):
Age MTX
≥ 1 y < 2 y 8 mg
≥ 2 y < 3 y 10 mg
≥3y 12 mg

4.4 Interval therapy - VLR
4.4.1 Conditions for starting of interval therapy
6-MP is started 14 days after completion of protocol I. Leukocytes > 1.5 x 109/l, PMN > 0.5x109/l and platelets
> 50 x109/l are required.
4.4.2 Design
In this 56 days phase, patients will receive daily 6-MP and 4 HD-MTX courses.
Number of
administrations
6-MP 25 mg/m² P.O. 56 1 to 56
HD-MTX* 5 g/m² ** I.V. (24h) 4 8, 22, 36 and 50
I.T. chemotherapy
See below *** I.T. 4 9, 23, 37 and 51
(MTX)
After each MTX
Leucovorin* 15 mg/m²/6h P.O. or I.V. ≥4
course H42
NOTES:
* For HD-MTX and leucovorin administration, see 9. Practical guidelines
** Down’s syndrome: the first Intermedaite dose MTX is only 0.5 g/m². This intermediate dose of MTX
can be increased to higher MTX doses if the patient shows good tolerance for the intermediate dose of
MTX.
*** Intrathecal chemotherapy (methotrexate)
Age MTX
≥ 1 y < 2 y 8 mg
≥ 2 y < 3 y 10 mg
≥3y 12 mg

4.5 Protocol II Reduced – VLR (Reinduction or Late intensification)
4.5.1 Conditions for starting protocol II Reduced
Protocol IIa is started 14 days after completion of interval therapy if the leukocytes are > 1.5 x 109/l
granulocytes are > 0.5 x 109/l and platelets > 50x109/l, and if the cell counts are increasing. If these counts are
lower, one has to wait until these values are reached.
Starting conditions for II b are described in the section 9
4.5.2 Design
Number
Drugs Dose/day Route Days
of days
DXM 6 mg/m² P.O. 21 1 to 21
1.5 mg/m²
VCR I.V. 4 8, 15, 22, 29
IIb (Maximum: 2.0 mg per injection)
ADR 30 mg/m² I.V. (1 h) 2* 8, 15
L-A'ase ** 10,000 U/m² I.V. (1 h) 4 8, 11, 15, 18
38 to 41
45 to 48
6-TG 60 mg/m² P.O. 14 36 to 49
IIb
I.T.
see below *** I.T. 1 38, 45
chemotherapy
NOTES:
* VLR patients receive 2 injections only of adriamycin and no cyclophosphamide

** For adjustment of L-A’ase treatment: see 9. Practical guidelines
*** Intrathecal chemotherapy (methotrexate):
Age MTX
≥ 1 y < 2 y 8 mg
≥ 2 y < 3 y 10 mg
≥3y 12 mg
4.6 Maintenance therapy - VLR

4.6.1 Conditions for starting maintenance
Starts 14 days after completion of protocol II and must be of 74 weeks duration.
4.6.2 Design
6-MP: 50 mg/m²/day, P.O. in one administration, in the evening

MTX: 20 mg/m²P.O., once a week

5 Average risk 1 (AR1)
5.1 Prephase - AR1
5.1.1 Design
Number of
days
PDN P.O.
60 mg/m²
or or 7 1 to 7
(30 mg/m² bid)
NOTES:
* Doses of MTX:
Age MTX
≥ 1 y < 2 y 8 mg
≥ 2 y < 3 y 10 mg
≥3y 12 mg
Detailer les IT si CNS 2 ou 3 ou TLP+ nog zeker aanvullen !!
5.1.2 In case of CNS involvement
The following patients will be treated as AR1:
- Patients VLR or AR1 with initial CNS2 becoming CSF negative (= “late” CNS1) at D4 of prephase
- Patients VLR and AR1 with initial TLP + becoming CSF negative (= “late” CNS1) at D4 of prephase
See more details in section 11 of these guidelines "Definition and Treatment of Extra-Medullary Involvement ”
5.2 Protocol I A (Induction) – AR1

5.2.1 Design
Drugs Number
Dose Route Days
of days
PDN 60 mg/m² P.O. 21 8 to 28
1.5 mg/m²
VCR I.V. 4 8, 15, 22 and 29
DNR 30 mg/m² I.V. (1 h) 4 8, 15, 22 and 29
Triple I.T.
For initial CNS 1 I.T. 2 12, 25*
chemotherapy
Triple I.T. For “late CNS1” and for “TPL+
I.T. 2 12, 18, 25*
chemotherapy and late CNS1”
12, 15, 18, 22, 25,
L-A'ase ** 10,000U/m² I.V (1 h) 8
29, 32 and 35
NOTES:
* the IT is preferably never given on the same day of a vincristine injection. However if the hospital has
clear and safe procedures to prevent mistakes in delivering intrathecal medications, the dates of
intrathecal injections can be also Day 8, (Day18) and Day 22
* Triple I.T. chemotherapy
Age MTX Ara-C Hydrocortisone

≥ 1 y < 2 y 8 mg 20 mg 10.0 mg
≥ 2 y < 3 y 10 mg 25 mg 12.5 mg
≥3y 12 mg 30 mg 15.0 mg
If no hydrocortisone for IT uses is available (Belgium) the hydrocortisone can be replaced by an other
corticosteroid (in adapted or equivalent doses)
5.3 Protocol I B (Consolidation) – AR1

5.3.1 Conditions for starting I B (theoretically on day 36)
- Complete remission is confirmed.

- PMN > 1.0x109/l and platelets > 100x109/l and peripheral blood counts are increasing.
5.3.2 Design
Number
of days
Cyclophosphamide 1 g/m²* I.V. (1 h) 2 36 and 63
6-MP 60 mg/m² P.O. 28 36 to 63
38 to 41,
45 to 48,
52 to 55,
59 to 62
Triple I.T.
see below** I.T. 2 38, 52
Chemotherapy
NOTES:
* I.V. over 1 h. MESNA: I.V. bolus: 350 mg/m² at H0, H4 and H8
** Triple I.T. chemotherapy

≥ 1 y < 2 y 8 mg 20 mg 10.0 mg
≥ 2 y < 3 y 10 mg 25 mg 12.5 mg
≥3y 12 mg 30 mg 15.0 mg

5.4 Interval therapy – AR1
5.4.2 Design
In this 56 days phase, patients will receive daily 6-MP and 4 HD-MTX courses
Number of
administrations
6-MP 25 mg/m² P.O. 56 1 to 56
HD-MTX* 5 g/m² ** I.V. (24 h) 4 8, 22, 36 and 50
Triple I.T.
see below *** I.T. 4 9, 23, 37 and 51
Chemotherapy
After each MTX
Leucovorin 15 mg/m²/6h P.O. or I.V. ≥4
course H42
NOTES:
** Down’s syndrome: the first Intermedaite dose MTX is only 0.5 g/m². This intermediate dose of MTX
can be increased to higher MTX doses if the patient shows good tolerance for the intermediate dose of
MTX.
*** Triple I.T. chemotherapy

≥ 1 y < 2 y 8 mg 20 mg 10.0 mg
≥ 2 y < 3 y 10 mg 25 mg 12.5 mg
≥3y 12 mg 30 mg 15.0 mg

5.5 Protocol II – AR1 (Reinduction or Late Intensification)
5.5.1 Conditions for starting protocol II
Protocol II is started 14 days after completion of interval therapy if the leukocytes are > 1.5 x 109/l granulocytes
are > 0.5 x 109/l and platelets > 50x109/l, and if the cell counts are increasing. If these counts are lower, one has
to wait until these values are reached.
Starting conditions for II B are described in the section 9
5.5.2 Design
Number
of days
DXM 6 mg/m² P.O. 21 1 to 21
1.5 mg/m²
VCR (maximum dose per I.V. 4 8, 15, 22, 29
IIA
injection 2.0 mg)
ADR 30 mg/m² I.V. (1 h) 4 8, 15, 22, 29
L-A'ase* 10,000 U/m² I.V. (1 h) 4 8, 11, 15, 18
Cyclophosphamide 1 g/m² I.V. (1 h) 1 36
38 to 41
45 to 48
IIB
6-TG 60 mg/m² P.O. 14 36 to 49
Triple I.T
see below** I.T. 1 38, 45
chemotherapy
NOTES:
* For adjustment of L-A’ase treatment: see 9. Practical guidelines

≥ 1 y < 2 y 8 mg 20 mg 10.0 mg
≥ 2 y < 3 y 10 mg 25 mg 12.5 mg
≥3y 12 mg 30 mg 15.0 mg

5.6 Maintenance therapy – AR1
5.6.2 Design
The first 60 weeks of maintenance therapy are subdivided in 6 periods of 10-week duration each (or 70 days).
Within each of these periods, the treatment is as follows:
Number
Drug Dose Route Days
of days
6-MP 50 mg/m² P.O. 70 1 to 70
1, 8, 15, 29, 36, 43, 50, 57,
MTX 20 mg/m² P.O. 9
64
Triple I.T.
See below* I.T. 1 22
chemotherapy
1.5 mg/m²
VCR I.V. 2 57, 64
DXM 6 mg/m² P.O. 7 57 to 63
NOTES:
* Triple I.T. chemotherapy

≥ 1 y < 2 y 8 mg 20 mg 10.0 mg
≥ 2 y < 3 y 10 mg 25 mg 12.5 mg
≥3y 12 mg 30 mg 15.0 mg
After the 6 cycles, further maintenance chemotherapy will consist of:
- 6-MP: 50 mg/m²/day, P.O. in one administration, in the evening

- MTX: 20 mg/m², P.O. once a week

6 Average risk 2 (AR2) - B-cell ALL
6.1 Prephase – AR2-B
6.1.1 Design
Number of
days
PDN P.O.
60 mg/m²
or or 7 1 to 7
(30 mg/m² bid)
methyl-PDN I.V. (1 h)
NOTES:
* Doses of MTX:
Age MTX
≥ 1 y < 2 y 8 mg
≥ 2 y < 3 y 10 mg
≥3y 12 mg
The following patients with B ALL will be treated as AR 2 – B ALL:
- VLR and AR1 Patients with CNS3 at D1 or any CNS involvement at D1 (see diagnostic definitions)
- VLR and AR1 Patients with CNS2 or TLP+ at D1 AND any CSF involvement at D4 (= Late CNS 3)
See more details in section 11 of these guidelines "Definition and Treatment of Extra-Medullary Involvement ”

6.2 Protocol I A Augmented – AR2-B (Induction)
6.2.1 Design
Number of
days
DXM 6 mg/m² P.O. 21 8 to 28
I.V. (24
HD-MTX* 5 g/m² 1 8
h)
Cyclophosphamide** 1 g/m² I.V. (1 h) 1 9
1.5 mg/m²
VCR (maximum dose per injection I.V. 4 8, 15, 22 and 29
2.0 mg)
DNR 40 mg/m² I.V. (1 h) 3 15, 22 and 29
Triple I.T*** No CNS involvement I.T. 2 9, 25
Triple I.T*** With CNS involvement

I.T. 4 9, 18, 25**
12, 15, 18, 22, 25, 29, 32
L-A'ase**** 10,000 U/m² I.V. (1h) 8
and 35
NOTES:
** I.V. over 1 h. MESNA: I.V. bolus: 350 mg/m² at H0, H4 and H8
*** the IT is preferably never given on the same day of a vincristine injection. However if the hospital has
clear and safe procedures to prevent mistakes in delivering intrathecal medications, the date of intrathecal
injections can be also Day 22
*** Triple I.T. chemotherapy (in case of CNS involvement: see recommendations)

≥ 1 y < 2 y 8 mg 20 mg 10.0 mg
≥ 2 y < 3 y 10 mg 25 mg 12.5 mg
≥3y 12 mg 30 mg 15.0 mg
*** For adjustment of L-A’ase treatment: see 8. Practical guidelines

6.3 Protocol I B – AR2-B (Consolidation)
6.3.1 Conditions for starting IB (theoretically on day 36)
- Complete remission is confirmed. There is no VHR feature.

- PMN > 1.0x109/l and platelets > 100x109/l and are increasing.
6.3.2 Design
Number
of days
Cyclophosphamide 1 g/m²* I.V. 2 36 and 63
6-MP 60 mg/m² P.O. 28 36 to 63
38 to 41,
45 to 48,
52 to 55,
59 to 62
Triple I.T.
See below ** I.T. 2 38, 52
chemotherapy
NOTES:


≥ 1 y < 2 y 8 mg 20 mg 10.0 mg
≥ 2 y < 3 y 10 mg 25 mg 12.5 mg
≥3y 12 mg 30 mg 15.0 mg
6.4 Interval therapy – AR2-B

6.4.2 Design
In this 56 days phase patients will receive daily 6-MP and 4 HD-MTX courses
Number of
administrations
6-MP 25 mg/m² P.O. 56 1 to 56
HD-MTX* 5 g/m² I.V. (24 h) 4 8, 22, 36 and 50
Triple I.T.
See below ** I.T. 4 9, 23, 37 and 51
chemotherapy
After each MTX
Leucovorin 15 mg/m²/6h P.O. or I.V. ≥4
course H42
NOTES:

≥ 1 y < 2 y 8 mg 20 mg 10.0 mg
≥ 2 y < 3 y 10 mg 25 mg 12.5 mg
≥3y 12 mg 30 mg 15.0 mg
6.5 Protocol II - – AR2-B (Reinduction or Late intensification)

6.5.2 Design
Number of
days
DXM 6 mg/m² P.O. 21 1 to 21
1.5 mg/m²
VCR I.V. 4 8, 15, 22, 29
(Maximum : 2.0 mg per injection)
ADR 30 mg/m² I.V. (1 h) 4 8, 15, 22, 29
IIA
L-A'ase* 10,000 U/m² I.V. (1 h) 4 8, 11, 15, 18
Only in case of initial
Triple I.T
CNS involvement I.T. 2 1, 18
chemotherapy
see below for dose **
Cyclophosphami
1 g/m² I.V. (1 h) 1 36
de
38 to 41
IIB 45 to 48
6-TG 60 mg/m² P.O. 14 36 to 49
Triple I.T
I.T. 2 38, 45
chemotherapy see below**
NOTES:

≥ 1 y < 2 y 8 mg 20 mg 10.0 mg
≥ 2 y < 3 y 10 mg 25 mg 12.5 mg
≥3y 12 mg 30 mg 15.0 mg
6.6 Maintenance therapy – AR2-B
6.6.2 Design
The first 60 weeks of maintenance therapy are subdivided in 6 periods of 10-week duration each (or 70 days).
Within each of these periods, the treatment is as follows:
Drug Dose Route Number of days Days

6-MP * 50 mg/m² P.O. 70 1 to 70
1, 8, 15, 29, 36, 43,
MTX * 20 mg/m² P.O. 9
50, 57, 64
HD-MTX** 5 g/m² I.V. (24 h) 1 22
Leucovorin** 15 mg/m²/6h P.O.or I.V. 2 23-24
Triple I.T
see below *** I.T. 1 23
chemotherapy
L-A’ase**** 25,000 U/m² I.V. (1 h) 1 23
1.5 mg/m²
VCR (Maximum : 2.0 mg per I.V. 2 57,64
injection)
6 mg/m²
DXM P.O. 7 57 to 63
(3 mg/m² BID)
NOTES
* see 9. Practical guidelines
** For HD-MTX and leucovorin administration, see 9. Practical guidelines

≥ 1 y < 2 y 8 mg 20 mg 10.0 mg
≥ 2 y < 3 y 10 mg 25 mg 12.5 mg
≥3y 12 mg 30 mg 15.0 mg
**** For adjustment of L-A’ase treatment: see 9. Practical guidelines
After the 6 cycles, further maintenance therapy will consist of
- 6-MP: 50 mg/m²/day P.O. in one administration, in the evening

- MTX: 20 mg/m²/day P.O. once a week

7 Average risk 2 (AR2) - T-cell ALL
7.1 Prephase – AR2-T
7.1.1 Design
Number of
days
PDN P.O.
60 mg/m²
or or 7 1 to 7
(30 mg/m² bid)
NOTES:
* Doses of MTX:
Age MTX
≥ 1 y < 2 y 8 mg
≥ 2 y < 3 y 10 mg
≥3y 12 mg
Note that only the T ALL patients who have no CNS involvement will be treated as AR 2 – T ALL.
See more details in section 11 "Definition and Treatment of Extra-Medullary Involvement ”

7.2 Procotol I A - AR2-T (Induction)
7.2.1 Design
Number
of days
10 mg/m²
DXM (5 mg/m² BID) P.O. 21 8 to 28
(Maximum dose: 15 mg per day)
1.5 mg/m²
VCR (Maximum: 2.0 mg per I.V. 4 8, 15, 22 and 29
injection)
DNR 30 mg/m² I.V. (1 h) 4 8,15, 22 and 29
Triple
No CNS involvement * I.T. 2 12, 25*
I.T.chemotherapy*
Triple For “late CNS1” and for “TPL+
I.T. 2 12, 18, 25*
I.T.chemotherapy* and late CNS1”
12, 15, 18, 22, 25,
L-A'ase** 5.000 U/m² I.V. (1 h) 8
29, 32 and 35
NOTES:
* In case of CNS involvement: always VHR
* the IT is preferably never given on the same day of a vincristine injection.

However if the hospital has clear and safe procedures to prevent mistakes in delivering intrathecal medications,
the dates of intrathecal injections can be also Day 8 and Day 22
Triple I.T. chemotherapy (in case of CNS involvement: always VHR)

≥ 1 y < 2 y 8 mg 20 mg 10.0 mg
≥ 2 y < 3 y 10 mg 25 mg 12.5 mg
≥3y 12 mg 30 mg 15.0 mg
7.3 Protocol I B - AR2-T (Consolidation)

7.3.1 Conditions for starting IB (theoretically on day 36)
- Complete remission or good partial response is confirmed.

- PMN > 1.0x109/l and platelets > 100x109/l and peripheral blood count are increasing.

7.3.2 Design
Number
of days
Cyclophosphamide 1 g/m²* I.V. (1h) 2 36 and 63
6-MP 60 mg/m² P.O. 28 36 to 63
38 to 41,
45 to 48,
52 to 55,
59 to 62
Triple I.T.
See below ** I.T. 2 38, 52
chemotherapy
NOTES:

≥ 1 y < 2 y 8 mg 20 mg 10.0 mg
≥ 2 y < 3 y 10 mg 25 mg 12.5 mg
≥3y 12 mg 30 mg 15.0 mg
7.4 Interval therapy - AR2-T

7.4.2 Design
In this 56 days phase patients will receive daily 6-MP and 4 HD-MTX courses
Number of
administrations
6-MP 25 mg/m² P.O. 56 1 to 56
HD-MTX* 5 g/m² I.V. (24 h) 4 8, 22, 36 and 50
Triple I.T.
See below ** I.T. 4 9, 23, 37 and 51
chemotherapy
After each MTX
Leucovorin* 15 mg/m²/6h P.O. or I.V. ≥4
course start at H42
NOTES:

≥ 1 y < 2 y 8 mg 20 mg 10.0 mg
≥ 2 y < 3 y 10 mg 25 mg 12.5 mg
≥3y 12 mg 30 mg 15.0 mg
7.5 Protocol II - AR2-T (Reinduction or Late intensification)

7.5.2 Design
Number
of days
10 mg/m² (max dose of
DXM 15mg/day) P.O. 21 1 to 21
(5 mg/m² BID)
IIA 1.5 mg/m²
VCR I.V. 4 8, 15, 22, 29
(Max : 2.0 mg per injection)
ADR 30 mg/m² I.V. (1 h) 4 8, 15, 22, 29
L-A'ase* 10.000 U/m² I.V. (1 h) 4 8, 11, 15, 18
Cyclophosphamide** 1 g/m² I.V. (1 h) 1 36
38 to 41
45 to 48
IIB
6-TG 60 mg/m² P.O. 14 36 to 49
Triple I.T
see below*** I.T. 1 38, 45
chemotherapy
NOTES:

≥ 1 y < 2 y 8 mg 20 mg 10.0 mg
≥ 2 y < 3 y 10 mg 25 mg 12.5 mg
≥3y 12 mg 30 mg 15.0 mg

7.6 Maintenance therapy - AR2-T
The first 60 weeks of maintenance therapy are subdivided in 6 periods of 10-week duration each (or
70 days). Within each of these periods, the treatment is as follows:
Number of
administrations
6-MP* 50 mg/m² P.O. 70 1 to 70
1, 8, 15, 29, 36, 43,
MTX* 20 mg/m² P.O. 9
50, 57, 64
HD-MTX** 5 g/m² I.V. (24 h) 1 22
Leucovorin** 12 mg/m²/6h P.O. or I.V. 2 23, 24
Triple I.T
see below*** I.T. 1 23
chemotherapy
L-A’ase**** 25,000 U/m² I.V. (1 h) 1 23
NOTES:
* see 9. Practical guidelines

≥ 1 y < 2 y 8 mg 20 mg 10.0 mg
≥ 2 y < 3 y 10 mg 25 mg 12.5 mg
≥3y 12 mg 30 mg 15.0 mg
**** For adjustment of L-A’ase treatment: see 8. Practical guidelines
After the 6 cycles, further maintenance therapy will consist of

6-MP : 50 mg/m²/day, p.o. in one administration, in the evening
MTX : 20 mg/m², p.o. once a week
Duration of Maintenance for AR2-T ALL:
In progenitor B ALL we presume that the total duration of the maintenace treatment must be given.
Therefor we advise in progenitor B ALL to catch up the lost weeks of maintenance untill the full 74
weeks are given.
There is however less evidence that this in necessary for T ALL and we advise here to stick to a total
duration of treatment of exactely 2 year

8 Very high risk (VHR)
General Schema
Indications for SCT will added in Chapter 12
8.1 Prephase – VHR

8.1.1 Design
Number of
days
PDN P.O.
60 mg/m²
or or 7 1 to 7
(30 mg/m² bid)
NOTES:
* Doses of MTX:
Age MTX
≥ 1 y < 2 y 8 mg
≥ 2 y < 3 y 10 mg
≥3y 12 mg
See more details in the section 11 :
- «Evaluation of leukemic involvement of the CSF»
- « Definition of CNS involvement » (cf definitions)

8.2 Protocol I A – VHR (Induction)
8.2.1 Design
Drugs Number of
Dose Route Days
days
60 mg/m²
PDN P.O. 21 8 to 28
(30 mg/m² BID)
1.5 mg/m²
VCR I.V. 4 8, 15, 22 and 29
(Max: 2.0 mg per injection)
DNR 30 mg/m² I.V. (1 h) 4 8, 15, 22 and 29
Cyclophosphamide* 1 g/m² I.V. (1 h) 1 8
Triple I.T** No CNS involvement
I.T. 2 12, 25
Triple I.T** WITH CNS involvement
I.T. 4 12, 18, 25
12, 15, 18, 22, 25, 29,
L-A'ase *** 10,000 U/m² I.V. 8
32 and 35
NOTES:
** the IT is preferably never given on the same day of a vincristine injection.

However if the hospital has clear and safe procedures to prevent mistakes in delivering intrathecal medications,
the dates of intrathecal injections can be also Day 8 and Day 22
Triple I.T. chemotherapy

≥ 1 y < 2 y 8 mg 20 mg 10.0 mg
≥ 2 y < 3 y 10 mg 25 mg 12.5 mg
≥3y 12 mg 30 mg 15.0 mg
8.3 Treatment of VHR patients beyond protocol IA

VHR patients are defined according to the criteria of inclusion.
These patients are so defined either at the end of the prephase (poor response) or during phase IA
(immunophenotyping and cytogenetics results) or at completion of phase IA (resistance or no response) or at
the latest during the first two weeks of IB Lyon (MRD). They all have received phase IA. Subsequent treatment
phases for all VHR patients are reinforced consolidation (IB Augmented), and VANDA. Those VHR patients
who meet the eligibility criteria for stem cell transplantation (SCT) and who have a HLA compatible familial or
compatible unrelated donor will be transplanted.
VHR patients who do not meet the criteria for SCT will receive intensified chemotherapy for a total treatment
duration of two years (see general design, on the next page).
The different phases of the VHR regimen (except the Interval and the Maintenance phases) may induce severe
and prolonged aplasia.
8.4 Protocol I B augmented – VHR (1° Consolidation)
8.4.1 Conditions for starting I B augmented (theoretically D 36)
- Complete remission confirmed or not
- VHR features are present
- PMN > 1.0x109/l, platelets > 100x109/l (not required if CR is not achieved).
8.4.2 Design
Number
of days
Cyclophosphamide 1 g/m² I.V. (1 h) 2 1, 29
1 to 14
6-MP 60 mg/m² P.O. 28
29 to 42
3,4,5,6,
10,11,12,13
ARA-C 75 mg/m² I.V. 16
31,32,33,34
38,39,40,41
1.5 mg/m²
VCR* I.V. 2 15 and 22
(Max: 2.0 mg per injection)
HD-MTX** 5 g/m² I.V. (24 h) 1 15
Triple I.T.
see below *** I.T. 3 3,16,31
chemotherapy
Leucovorin** 15 mg/m² I.V. or P.O. >4 16, H42 post MTX
L-A’ase 6000 U/m²**** I.V. (1h) 6 16,18,20,22,24,26
NOTES:
* VCR on day 15 to be given before MTX
*** Triple I.T. chemotherapy: 24 h after the beginning of the iv MTX infusion.

<1y 6 mg 15 mg 7.5 mg
≥ 1 y < 2 y 8 mg 20 mg 10.0 mg
≥ 2 y < 3 y 10 mg 25 mg 12.5 mg
≥3y 12 mg 30 mg 15.0 mg
**** For adjustment of L-A’ase treatment: see 9. Practical guidelines. In case of allergy for Aspa Coli the
frequency of the injections with Aspa Erwinia does not increase (n=6) due to the timeline.

8.5 Protocol VANDA – VHR (2° Consolidation)
8.5.1 Conditions for starting VANDA
- Complete remission is confirmed
- patient is recovering from phase I B’
- PMN > 1.0x109/l, platelets > 100x109/l
8.5.2 Design
Number of
administrations
20 mg/m² *
DXM P.O. 10 1 to 5
( 10 mg/m² BID)
ARA-C 2 g/m²/12 h I.V. (3 h) 4 1 and 2
MTZ 8 mg/m² I.V. 2 3 and 4
VP 16 150 mg/m² I.V. (1 h) 3 3, 4 and 5
Triple I.T.
See below ** 1 5
chemotherapy
L-A'ase 10,000 U/m² *** I.V. 4 7, 9, 11 and 13
* the dose of Dexa is NOT limited to 15 mg/day
** Triple I.T. chemotherapy:

≥ 1 y < 2 y 8 mg 20 mg 10.0 mg
≥ 2 y < 3 y 10 mg 25 mg 12.5 mg
≥3y 12 mg 30 mg 15.0 mg
8.6 1° Interval therapy– VHR : 3 cures of HDMTX

8.6.1 Conditions for starting Interval therapy
Open Question
Recovering from VANDA:: WBC > 1.5x109/l,

PMN > 0.5 x109/l, platelets > 50x109/l

8.6.2 Design
The total duration of the course is 42 days only, and 3 HD-MTX courses only are given.
Nbr of
administrations
6-MP 25 mg/m² P.O. 42 1 to 42
HD-MTX * 5 g/m² I.V. (24 h) 3 8, 22 and 36
after each MTX course,
Leucovorin * 15 mg/m²/6h P.O. or I.V. ≥4
at H42
Triple I.T.
See below ** I.T. 3 9, 23 and 37
chemotherapy
NOTES:
** Triple I.T. chemotherapy:

≥ 1 y < 2 y 8 mg 20 mg 10.0 mg
≥ 2 y < 3 y 10 mg 25 mg 12.5 mg
≥3y 12 mg 30 mg 15.0 mg
8.7 Protocol II modified – VHR ( 1° Reinduction or 1° Late

Intensification)
Number of
days
6 mg/m²
DXM P.O. 21 1 to 21
(3 mg/m² BID)
1.5 mg/m²
VCR I.V. 4 8, 15, 22, 29
IIA (Max : 2.0 mg per injection)
mod ADR 25mg/m² I.V. (1 h) 3* 8, 15, 22
L-A'ase** 10,000 U/m² I.V. 4** 8, 11, 15, 18
Only in case of CNS
Triple I.T. I.T. 1 1, 18
involvement
Cyclophosphamide 1 g/m² I.V. (1 h) 1 36
38 to 41
IIB 45 to 48
6-TG 60 mg/m² P.O. 14 36 to 49
Triple I.T. see below *** I.T. 2 38, 45
NOTES
* Only 3 injections of adriamycine at 25 mg/m²
** For adjustment and monitoring of L-A’ase treatment: see 9. Practical guidelines

8.8 2° Interval therapy – VHR: 3 cures of HDMTX
See 8. 6. Interval therapy
8.9 Protocol II modified – VHR ( 2° Reinduction or 2° Late

Intensification)
See 8. 7 Protocol II modified
8.10 Maintenance therapy – VHR

Starts 14 days after completion of protocol II modified and ends at 2 years after day 1 of the treatment.
8.10.2 Design
maintenance chemotherapy will consist of:
- 6-MP: 50 mg/m²/day, P.O. in one administration, in the evening

- MTX: 20 mg/m², P.O. once a week
8.10.3 Duration of Maintenance:
In progenitor B ALL we presume that the total duration of the maintenace treatment must be given.
Therefor we advise in progenitor B ALL to catch up the lost weeks of maintenance untill the full 74
weeks are given.
There is however less evidence that this in necessary for T ALL and for VHR patients. We advise here
to stick to a total duration of treatment of exactely 2 year

9 Practical guidelines
9.1 Prephase
- PDN or methyl-PDN are given in two doses a day. If administered I.V., corticosteroids (methyl-PDN)
should be injected over 1 hour.
- In case of important leukemic burden and blast counts remaining unchanged or increasing by
Day 4 the administration of cyclophosphamide can be advanced to day 4 and day 5 in the dosage
of 500 mg/m2 on each of the two days. The patient will of course follow the VHR protocol (PPR)
9.2 Induction (IA reduced, IA, IA augmented)
- PDN or DXM are given in two doses a day (Bis in Diem or BID). After day 28 they are tapered down
over 9 days. The maximum dose of DXM per day is 15 mg.
- Vincristine (VCR) is given as an intravenous bolus or in mini-bag, concomitantly with DNR. In case
the DNR has to be postponed, VCR will also be given later. The dose of VCR is 1.5 mg/m², with a
maximum dose of 2.0 mg.
- Daunorubicin (DNR) is given over 1 hour, as an I.V. infusion.
- HD-MTX 5 g/m² is administered as described for interval therapy.
- Cyclophosphamide is given I.V. over 1 h and MESNA is given as an I.V. bolus 350 mg/m2
respectively at H0, H4 and H8.
- L-asparaginase: E. Coli is given intravenously as a 1-hour infusion. The treatment should start with E.
Coli asparaginase. In case of allergy grade 2 or more during the course, one should switch over to
Erwiniase at the dose of 20,000 U/m² every other day (see Table 1).
Table Protocol Aspa adaptations – all “Non AR2 – T” patients: Instructions for switch from native E
coli asparaginase to Erwiniase,
Treatment E.Coli asparaginase ERWINIASE

IA 10.000 U/m² x 8 20.000 U/m² x 12
IIA 10.000 U/m² x 4 20.000 U/m² x 6
Maint (AR2) 25.000 U/m² x 1 25.000 U/m² x 2
IB augmented 10.000 U/m² x 6 20.000 U/m² x 6
VANDA 10.000 U/m² x 4 20.000 U/m² x 6

Table Protocol Aspa Adaptations “AR2 - T” only: Instructions for switch from native E coli
asparaginase to Erwiniase,
Treatment E.Coli asparaginase ERWINIASE

IA 5.000 U/m² x 8 10.000 U/m² x 12*
IIA 10.000 U/m² x 4 20.000 U/m² x 6
Maint (AR2) 25.000 U/m² x 1 25.000 U/m² x 2
The total number of Erwiniase administrations should be one and a half that of the E. Coli asparaginase
administrations. For instance, if four E. Coli asparaginase administrations had still to be given and were
to be replaced by Erwiniase, 6 injections of the latter will be done within the same total time period. In
centers where E. Coli asparaginase is not available, 12 injections of Erwiniase (20,000 U/m²) will be
given during IA (day 12 to 35).
Cautious monitoring of body weight, glycaemia, glycosuria, clotting factors (fibrinogen) and complete
ionogram with plasma level of proteins are required during L-A’ase treatment. Treatment adjustment
should be as follows:
o fibrinogen ≥ 0.5 g/l: full dose of L-A’ase
o fibrinogen < 0.5 g/l: either postponement of the next L-A’ase administration or substitutive
treatment with inactivated fresh frozen plasma (10 ml / kg) will be administered until fibrinogen
level is restored (> 0.5 g/l). NB. Substitution should not be done with fibrinogen alone.
Treatment adjustments according to other criteria (AT, total plasma protein level, transaminases) are
optional in each center.
Diabetes mellitus can occur during treatment with L-A’ase and corticosteroids. Insulin therapy may be
necessary. However L-A’ase treatment should be continued.
If Erwiniase is not available and if, for a reason other than allergy to the native E. Coli asparaginase, a
switch to a pegylated form of E. Coli Asparaginase is considered, the following doses and schedule of
administration of PEG asparaginase should be used (see Table 2).
Table 2. Instructions for switch from native E coli asparaginase to PEG- asparaginase
Treatment E.Coli asparaginase PEG- asparaginase
IA 10.000 U/m2 x 8 2.500 U/m2 (D12 and D26)
IIA 10.000 U/m2 x 4 2.500 U/m2 (D8)
Maint (AR2) 25.000 U/m2 x1 2.500 U/m2 (D23)
IB augmented 10.000 U/m2 x 6 2.500 U/m2 (D16)
VANDA 10.000 U/m2 x 4 2.500 U/m2 ( D7)
In patients having displayed an allergic reaction to the native E. Coli Asparaginase used in the USA it
has been shown that the plasmatic half life of the pegylated form of E. coli Asparaginase and its
efficiency (asparagines depletion) are markedly reduced. It is therefore possible that for this category of
patients a switch to the PEG asparaginase would be inefficient. However the available data concerning
E. Coli asparaginase from Medac as well as its pegylated derivate are insufficient to allow us to
recommend either an updated adjustment of dosing, a shorter interval between the administrations of
PEG asparaginase or the decision to disregard its use (Wang B, Relling MV, Storm MC, et al.
Evaluation of immunologic crossreaction of antiasparaginase antibodies in acute lymphoblastic
leukemia (ALL) and lymphoma patients (Leukemia (England), Aug 2003, 17(8) p1583-8).
- Cotrimoxazole (dose equivalent to 5 mg trimethoprim/kg/day, during 3 days a week) may be given as a

prophylaxis of Pneumocystis carinii pneumonia as soon as the lymphocyte count falls below 0.5x109/l,
and may be continued throughout the protocol according to the local risk for this infection as evaluated
by each investigator. It should not be given simultaneously with high dose methotrexate.
9.3 Consolidation (IB reduced and IB)
- Condition for VLR patients is different (no Cyclofosfamide) and starts with Cytosine arabinoside =
aracytine (Ara-C):, the first 4-day sequence starts if the leukocyte count is > 0.5 x 109/L. Once a ARA
–C block has been started, it should be pursued over four days whatever the further evolution of the
blood cell counts;.
- Conditions for starting IB (theoretically on day 36 with Cyclofosfamide ) for all non VLR
patients : PMN > 1.0 x 109/l and platelets > 100x109/l and are increasing.
- For AR1, AR2 and VHR patients, the first 4-day sequence starts 2 days after the CPM injection.
The following Arac-C blocks will be retarded if the leukocyte count is < 0.5 x 109/L or if the platelets
are < 20x109/L.. Retarding the Arac block means also that you stops the 6MP at the same time uitil the
Ara-C is restarted. Each Ara-C injection is in bolus.
Once it has been started, it should be pursued over four days whatever the further evolution of the blood
cell counts.
The same is true for the last block of Ara-C immediately followed by Cyclofosfamide. Once started the
last Ara C block the cyclofosfamide must be given without delay. In order to prevent severe aplasia at
the time of cyclophosphamide administration on day 63, it is a possible option to delay the starting of
the fourth Ara-C block until there are slighly higher counts than for an Ara C block alone: leukocytes
are > 1x109/L and the platelets > 50x109/L.
6-mercaptopurine (6-MP) p.o., once a day, in the evening.
9.4 1° Consolidation for VHR ( IB augmented)
- MTX: MTX is administered as a 24-hour intravenous infusion, with the same recommendations as in
interval therapy (see 5.4. Interval therapy).
- Leucovorin rescue: leucovorin is administered with the same recommendations as in interval therapy
(see 8.5. Interval therapy)
- L-asparaginase: E-coli is given by I.V. route. In case of allergy grade 2 or more, one should switch
over to Erwiniase, with the same recommendations as in phase IA (see 8.2. Protocol IA).
9.5 Interval therapy

- 6-MP: cumulative dose of 6-MP during this phase is 1.400 mg/m².
- MTX: MTX is administered as a 24-hour intravenous infusion. One tenth of the dose (500 mg/m²) is
given over the first hour. The remaining of the dose (4.500 mg/m²) is infused over the subsequent 23
hours at a constant rate.
Prior to the MTX infusion is hyperhydration unnecessary. However, urinary pH must be > 7 before
starting I.V.MTX. Alkalinisation is achieved through administration of bicarbonate, 1 mEq/kg, in 20 to
50 ml (according to age) of 5 % glucose solute over 15 minutes (1 ml of NaHCO3 4.2 % contains 1
mEq). Hyperhydration is started with the MTX infusion and is pursued during 72 h, at a rate of 3
L/m²/24h.
On the first day, hyperhydration is implemented intravenously with the following solute mixture:
o glucose 5 % : 2/3 of the total volume
o NaHCO3 (14°/∞): 1/3 of the total volume
o KCL 30 mEq/L
MTX can be mixed with this solution. On day 2 and day 3, in the absence of emesis, hyperhydration and
alkalinisation can be continued orally. During 72 hours starting from the beginning of MTX infusion,
hyperhydration and alkalinisation must be pursued in order for the diuresis to be maintained > 1.600
ml/m²/24 h and urinary pH > 7. Urinary pH must be measured on fresh urine immediately after each
voiding.
Whenever it becomes < 7, a booster alkalinisation is to be given through the administration of NaHCO3
1 mEq/kg in 50 ml of glucose 5 % over 15 minutes. Urinary pH tends to fall during the night and
monitoring should be particularly stringent at that time.
The triple intrathecal chemotherapy is given near the end of the MTX infusion.
- Leucovorin rescue: the first dose of Leucovorin at 15mg/m² is given 42 hours after the start of the
MTX-infusion (in the 951 study we had our first rescue dose at 36h) Following doses of 15 mg/m² each
are given at 6-hour interval until hour 72 or until MTX serum level has fallen to < 2 x 10-7 M. If MTX
levels are closely monitored, Leucovorin can often be stopped after 4 administrations. Leucovorin
should preferentially be given orally. If the per oral route cannot be used because of emesis, the drug is
given through I.V. bolus every 6-hours in the same dose.
In case Levofolinic acid is used, half dose is required (7,5 mg/m²).
• MTX levels are measured at 48 hrs and 72 hrs after the start of the MTX infusion. If the level dose at
48 hrs is to high and there is a need for a higher rescue dose it is recommended to measure also the
MTX level at 60hrs (with also an ionogram and ureum/creatinine)
• The dose of Leucovorin may have to be adjusted in case of protracted high serum MTX levels according
to the guidelines of table 3:
Table 3. Adjustments of Leucovorin doses to MTX serum levels and timing. (half dose if levofolinic
acid is used).
MTX/T 48 H 60 H 72 H 96 H > 96 H
> 1 x 10-5 4 x 50 mg/m² 4 x 50 mg/m² 4 x 200 mg/m² 4 x 200 mg/m² 4 x 200 mg/m²
< 2 x 10-7 0 mg 0 mg 0 mg 0 mg 0 mg
T = time since the start of MTX infusion

MTX = MTX serum level in moles/l (M)

9.6 Reinduction or Late Intensification (II reduced, II normal, II
modified)
- Dexamethasone (DXM) is given in two doses a day at the total daily dose of 6 mg/m² for B- ALL and
in AR2 – T ALL at 10mg/m² (with a maximum of 15 mg per day). After day 21, it is tapered down over
9 days. In case of severe behavioral difficulties, the tapering down may be started earlier.
- Vincristine (VCR) is given as an I.V. bolus, always on the same day as ADR. If ADR has to be
postponed, VCR will also be given later. The dose of VCR is 1.5 mg/m², with a maximum dose of 2.0
mg.
- Adriamycine (ADR) = doxorubicine is given over 1 hour, as an I.V. infusion.
- L-asparaginase (L-A’ase): E-Coli is given intravenously over one hour. In case of allergy grade 2 or
more to E. coli asparaginase, one has to switch over to Erwiniase (if available) at the dose of 20,000
U/m² per administration, the number of Erwiniase administrations being increased to one and half that
of the E.coli administrations. Practically, this means 3 administrations within a week.
- Cytosine arabinoside = aracytine (Ara-C): the first 4-day sequence starts 2 days after the CPM
injection. It is to be retarded if the leukocyte count is < 0.5 x 109/L. Retarding the Arac block means
also that you stops the 6TG at the same time uitil the Ara-C is restarted
Once it has been started, it should be pursued over four days whatever the further evolution of the blood
cell counts. Each Ara-C injection is in bolus.
- Cyclophosphamide (CPM) is given intravenously over 60 minutes, with MESNA (“Uromitexan”). The
latter drug is given in the same total dose as cyclophosphamide, divided in 3 administrations: a third of
the dose before the administration of CPM, a third at 4 hours and a third at eight hours.
Requirements for administration of CPM (= for starting IIB) are :
o Leukocytes > 1 x 109/L
o Platelets > 50 x 109/L
o Increasing blood counts
- 6-thioguanine (6-TG) is given every evening during 14 days. The same hematologic criteria as for
CPM are required for starting. The drug is interrupted if the leukocytes fall below 0.5 x 109/L. In the
latter case, the course will have to be prolonged until a cumulative dose of 840 mg/m² has been reached.
- I.T. chemotherapy is given on the day of the first Ara-C injection.
9.7 2° Consolidation VHR ( VANDA)
- DXM: P.O., 2 times/d. The dose is NOT limited to 15 mg/day

-
- ARA-C: 3 h I.V. infusion every 12 h, twice a day (total dose = 8 g/m2).
- MTZ (mitoxantrone): 1 h I.V. infusion
- VP 16: 1 h I.V. infusion

- L-A’ase: E-coli is given by I.V. route. In case of allergy grade 2 or more, one should switch over to
Erwiniase, with the same recommendations as in phase IA (see 8.2. Protocol IA).
9.8 Maintenance
- Purinethol (6-MP): 50 mg/m² P.O. in one administration, in the evening.
- Methotrexate (MTX): 20 mg/m² in one weekly per oral administration, except on week 4 when triple
I.T. chemotherapy is administered (for AR1, AR2 and VHR patients).
- Dexamethasone (DXM) is given in two divided doses, P.O.
- Vincristine (VCR) is given in bolus I.V. injection, 1.5 mg/m² (maximum dose 2.0 mg)
- High dose methotrexate (HD-MTX) with Leucovorin rescue is given as described under “8.4.
Interval”
- L-asparaginase is given either I.V. over one hour, after completion of HD-MTX. Front-line L-
asparaginase is E.coli asparaginase (Kidrolase in France, Paronal in Belgium). If for any reason
Erwiniase has to be given, the dose will be maintained at 25,000 U/m2 but given twice at 3 days interval
(d23, d26).
- Maintenance chemotherapy is not interrupted during the VCR + DXM pulses.

The dosage of 6-MP and of per oral MTX is to be adjusted to the leukocyte-count, either downward or
upward. It is recommended to tailor the dose in order to maintain the leukocyte count between 2 and
3x109/l. Following rule may be applied:
Leukocyte x 109/l % 6-MP dose % MTX dose

<1 0 0
1 - 1.999 50 100
2 - 2.999 100 100
3 - 3.999 125 100
4 or more 150 or more 125 or more
Severe lymphocytopenia does not occur very often. However, lymphocyte counts lower than 0.2x109/l
mandate a lowering of the 6-MP dose.
A marked increase of the leukocyte (neutrophils) count (> 10x109/l) may occur during the VCR +
corticosteroid pulses. The leukocyte count usually reverts to usual values shortly after completion of the
pulse. During the 2-week period starting at the initiation of the pulse, the increased leukocyte count should
not be taken into account for upward adjustment of the 6-MP or MTX dose. Indeed, this could result in
marked myelosuppression.
It is recommended to give all patients Cotrimoxazole (TMP-SMX) as Pneumocystis Carini ou Jiroveci

prophylaxis. The dose is calculated on the Trimethoprim (TMP at 5 mg/kg/day and is given in 2 doses per
day and during 3 days a week. It also better not coinciding with the day of MTX administration.

Duration of Maintenance :
For VLR and AR patients: the total duration of maintenance is 74 weeks. In case no delay has occurred in
the sequential administration of protocol I, Interval and protocol II, the theoretical duration of which is 30
weeks. Overall, maintenance therapy will be completed at 2 years of diagnosis.
If any delay has occurred, either during one of the pre-maintenance phases or during maintenance therapy,
the latter should be continued in order to encompass a total duration of 74 weeks as mentioned above.
There is however less evidence that this in necessary for T ALL and for VHR Patients we advise here to
stick to a total duration of treatment of exactely 2 year
VHR patients who will not be transplanted will receive the same maintenance treatment as VLR patients
(no IT and no pulses)

10 General drug information
10.1 Adriamycin (= Doxorubicin) (ADR)
Toxicity: local necrosis if extravasation occurs, bone marrow depression, particularly leucopenia (nadir at day
10-14), emesis lasting 1-2 days, mucositis leading to mouth and GI ulcers, “red urine” (usually 1-2 days),
hyperpigmentation of nail beds. Late toxicity, usually after a higher than 500 mg/m² cumulative dose:
cardiomyopathy with heart failure.
10.2 Asparaginase (L-A’ase)
Toxicity: anorexia, fever and chills, reversible hepatotoxicity, hypoalbuminemia, hypofibrinogenemia,

disturbance of exocrine pancreas function (steatorrhea) and of endocrine pancreas function (non-ketotic
hyperglycemia, glucosuria, diabetes, dehydration), allergic reactions including rash, wheezing, shock (in latter
case, usually after repeated use, more particularly following an interruption in the treatment; accordingly, the
greatest risk for allergy is to be expected at the start of protocol II). In case of anaphylaxis, one has to switch to
the other asparaginase. Results of EORTC 58881 trial have shown that per unit of in vitro activity, E. coli
asparaginase has a higher in vivo activity and toxicity. Switching from E. coli A’ase to Erwiniase requires an
increase in the dosage (from 10,000 to 20,000 U/m²) and in the frequency of administration (three times a week
rather than twice a week).
In the UK Erwinase is licensed for IV use and has directions to give as a bolus directly from reconstitution but
also clinicians often run as an infusion. In terms of administration, the current SPC (summary of product
characteristics) recommends a direct injection (bolus or push) by IV or IM routes, i.e. without dilution after
reconstitution with 1-2 mL of NaCl. Nevertheless, in real practices some hospitals dilute the reconstituted
product in 50-100 mL NaCl, and infuse the product within 1 hour. However, there are no stability data after
dilution.
Following reports from Germany, describing a precipitate forming in Erwinase after reconstitution and further
dilution for intravenous infusion, it was decided to exclude intravenous infusion as a means of administration
until further notice.
Intravenous injection, intramuscular injection and subcutaneous injection will remain as the recommended
routes of administration.
The solution should be administered within 15 minutes of reconstitution. If a delay of more than 15 minutes
between reconstitution and administration is unavoidable, the solution should be withdrawn into a glass or
polypropylene syringe for the period of the delay. In this case, the solution should be administered within 8
hours.
Regarding the use of PEG-asparaginase please refer to the guidelines specified in section 8.
10.3 Cyclophosphamide (CPM)
Toxicity: bone marrow depression (nadir at 7-14 days), alopecia, mucositis leading to mouth and GI ulcers, skin
rash, facial flushing during injection, eosinophilia, inadequate secretion of antidiuretic hormone (ISADH).
Hemorrhagic cystitis has to be prevented by hyperhydration and concomitant administration of MESNA.
10.4 Cytosine-arabinoside (ARA-C)
Toxicity: bone marrow depression, emesis, flue-like syndrome, fever, liver toxicity. With high doses: mucositis,
diarrhea, conjunctivitis, facial flushing, cerebellar ataxia.
10.5 Daunorubicin (DNR)
Toxicity: same as for Adriamycin (cf. 5.7.1.).
10.6 Etoposide (VP-16)
Toxicity: myelosuppression, emesis, diarrhea, mucitis, anorexia, alopecia, hypertension following rapid
intraveneous infusion. Transient liver functioin abnormalities. Anaphylactic-like reaction with fever, chills,
bronchospasm, dyspnea and tachycardia. Peripheral neuropathy.
10.7 Corticosteroids
Toxicity: fluid and salt retention, hypertension, hyperglycemia and glycosuria, potassium depletion, obesity,
psychic disturbances (euphoria or depression, irritability, psychotic symptoms), gastric ulcers, intracranial
hypertension coincident with tailing off and/or stopping of the course, aseptic bone necrosis.
10.8 Methotrexate (MTX)
Toxicity: depends on the dose and duration of exposure. Bone marrow depression and megaloblastosis,
mucositis leading to mouth and Gl ulcers, hepatotoxicity, osteoporosis, malabsorption, pneumonitis. More
particularly after high doses: precipitation in renal tubules, renal failure, severe mucositis, rash (“lobster
syndrome”), leucoencephalopathy. Interaction with numerous other drugs (salicylates, sulfonamides, etc.)
10.9 6-mercaptopurine (6-MP)
Toxicity: bone marrow depression, mouth ulcers, stomatitis, macular-papular rash, liver dysfunction.
Interaction with Allopurinol, which delays 6-MP metabolism and increases its potency.
10.10 6-thioguanine (6-TG)
Toxicity: bone marrow depression, mouth ulcers, stomatitis, liver dysfunction (hepatocellular or obstructive
liver disease), loss of vibration sensitivity and unsteady gait, diarrhea, mild atopic dermatitis.
If 6-TG is not available, 6-mercaptopurine in the same dose should be substituted for it.

10.11 Vincristine (VCR)
Toxicity: local necrosis if extravasation occurs. Peripheral neuropathy, paresis, jaw pain, muscle pain,
constipation, paralytic ileus, inadequate secretion of ADH, convulsions, alopecia, sleeplessness.
10.12 Vindesine (VDS)
Toxicity: local necrosis if extravasation occurs. Neurologic side effects are usually less severe and less
progressive than those observed with VCR. Paralytic ileus, constipation, finger paresthesia, loss of reflexes,
peripheral neuropathy, paresis, jaw pain, headache, convulsions. Bronchospasm with acute dyspnea. Alopecia.
Muscle pain. Granulopenia.

11 Definitions and treatment of initial extra-medullary
involvement
Introduction
The definitions used in these guidelines are based on the international accepted definitions. There are clear
definitions of CNS status concerning the CSF findings on the first lumbar puncture.
Apart from the CNS status there are also CNS involvement definitions (taking in to account other involvements).
Any Lumbar Punction (and centrainly the diagnostic lumbar punction) must be done under a stable hemostatic
condition.
• This means that the level of platelets shorly before lumbar punction must be at least > 50 000/mm³;
• The volume that must be injected with the medication must be not less than 6 ml (this is the same
volume that is redrawned during the punction.
• Just after the lumbar punction the patient must be brougt or stays in prone position during at least 1
hour.
Because it is important to avoid blood contamination in the lumbar first punction, it is of great importance that this
technical procedure is doen by an experienced physician.
11.1 Initial CNS status (CSF findings at Day 1)
For non-traumatic punctures, CNS status is defined as follows:
• CNS 1: nontraumatic puncture, ≤ 5 WBC/µl CSF without leukemic cells on cytospin.

• CNS 2: nontraumatic puncture, ≤ 5 WBC/µl CSF with identifiable leukemic cells on cytospin.
• CNS 3: nontraumatic puncture, > 5 WBC/µl CSF with identifiable leukemic cells on cytospin.
For traumatic lumbar punctures, CNS status is defined as follows:
A traumatic lumbar puncture (TLP) is defined as 10 or more erythrocytes/µl CSF or as CSF macroscopically
contaminated with blood. (see cytospin instructions below)
• TLP +: traumatic lumbar puncture with leukemic cells on cytospin.

• TLP - : traumatic lumbar puncture without leukemic cells on cytospin
11.2 “Late”CNS status (beyond the 1° IT injection)
• For patients with initial CNS2 at Day 1 (surreptitious involvement for CLG ).
• “Late CNS 1”: Patients with initial CNS 2 at day 1 becoming CNS 1 or TLP - at the second lumbar
puncture (mostly Day 4 of prephase)
• “Late CNS 3”: Patients with initial CNS 2 at day 1 remaining CNS 2 or becoming CNS 3 or TLP + at
the second lumbar puncture at the second lumbar puncture (mostly Day 4 of prephase)
• Patients with initial TLP + at Day 1
• “TLP+ Late CNS 1”: Patients with initial TLP+ becoming CNS 1 or TLP- at the second lumbar
punction (mostly Day 4 of prephase)
• “TLP+ Late CNS 3”: Patients with initial TLP+ remaining TLP+ or becoming CNS2 or CNS3 at the
second lumbar puncture (mostly Day 4 of prephase)
11.3 CNS involvement at diagnosis:
• “CNS 3” status, (all CNS 3 status, also the “Late” CNS 3)
OR
• Intracerebral or meningeal leukemic (proven or probably) mass seen on the MRI or CT scans
OR
• Cranial nerve palsy (irrespective of CSF or imaging findings)

11.4 Treatment of CNS involvement
11.4.1 Initial CNS involvement (see 10.1.3. CNS involvement definition):
Systemic treatment:
- VLR and AR1 with CNS involvement will receive AR2 group treatment.
- AR2 patients with CNS involvement and VHR patients receive the VHR treatment.
IT treatment:
Frequency of IT injections
- IT injections will be given every 4 days until complete “CNS” remission .
- Usually 2 or 3 injections suffice to induce “CNS” CR .
- If “CNS” CR is not obtained at day 9 (3th IT), there will be additional IT injections given and this will be
continued if necessary.
Intrathecal medication
- Patients will receive on Day 1 MTX alone . In the non CNS3 patients also the second IT is an MTX alone.
- For CNS 3 patients: it is however recommended to give on Day 4 a Triple IT
- Also the following IT injections will be Triples
- No CNS irradiation will be given during front line therapy.
Risk GROUP at diagnosis: TREATMENT according to:

VLR with Initial CNS involvement AR2-B
AR1 with Initial CNS involvement AR2-B
AR2 with Initial CNS involvement VHR
VHR with Initial CNS involvement VHR
11.4.2 Patients with CNS 2 status at day 1 (surreptitious involvement):
- an IT injection with MTX alone will be given on day 4.
- In case CNS 2 persists on day 4, patient will be further treated as a CNS3 patient.
- If no blast is found in the CSF on day 4, patients with this initially CNS 2 will be further treated as CNS 1.
However, patients initially allocated to VLR group, will receive AR1 treatment.
CNS 2 at D1
Treatment according to findings on D4
Risk GROUP at diagnosis: “Late CNS1” ( Day 4) “Late CNS3” ( Day 4)
VLR AR1 AR2-B
AR1 AR1 AR2-B
AR2 AR2 VHR
VHR VHR VHR
11.4.3 Patients with TLP (traumatic lumbar puncture) at day 1
IT injection with MTX alone will be given on day 4.
- If at least ONE blast is found on the CSF cytospin of day 4, whatever the number of erythrocytes within the
CSF, the patient will be further treated as if he had a CNS 3 status and cannot be allocated to either the
VLR or the AR1 groups. These patients have to be allocated to the AR2 or the VHR groups, according to
the usual eligibility criteria.
- If NO blast is found on the CSF cytospin of day 4, patients with initially TPL + will be further treated as
CNS1 but are excluded from VLR treatment group (patients initially allocated to the risk group in the table
VLR will receive AR1 treatment).
TRAUMATIC LUMBAR PUNCTURE at D1

Treatment according to findings on D4
Risk GROUP at diagnosis: TP+ “Late CNS1” ( Day 4) TP+ “Late CNS3” ( Day 4)
VLR AR1 * AR2-B
AR1 AR1 * AR2-B
AR2 AR2 * VHR
VHR VHR * VHR
• For “Late CNS 1” and “TLP + and Late CNS1” we have preferred to add a supplementary IT injection
after the CSF has become blast-free.
• The 951 prescribe already for these AR1 patients the 2 IT in the prephase (D1 and D4) and 2 IT during the
Induction. By adding one IT the following order of IT will be : D1, D4, D12, D18 and D25.
• This supplementary IT has been integrated in our Guidelines (see AR1 Induction)

11.5 Cytocentrifugation technique (cytospin) and instructions for
cerebro-spinal fluid (CSF)
as recommended by Dr AM. Manel and Dr MP. Pages for trial 58951 and modified in july 2010 by Dr S. Girard
(Hematology Laboratory, Hospital Edouard Herriot, Lyon).
1. Quantitative cytology
The CSF sample should be homogenized by slow up and down rotating mobilization of the tube.
Introduce the undiluted CSF sample into the upper compartment of the Nageotte’s cell.
Dilute a part of CSF sample in acetic blue (1/2) and introduce it in the lower compartment of the Nageotte’s
cell.
Let it stand for about 10 minutes in a humid room, then count the erythrocytes and the leucocytes along 4 bands.
The cumulated counts over the 4 bands, when divided by 5, provide the number of cells per mm³ (1 band = 1.25
mm³)
Particular cases
If the CSF appears hemorrhagic or trouble, or if the number of erythrocytes is > 200 per band, dilute the CSF
with normal saline solution.
2. Qualitative cytology
2.1. Cytospin
The CSF sample should be homogenized by slow up.
Whatever the leucocyte count (even if < 2/mm³), try to obtain 2 cytospin pellets.
Note that we have decided NOT to add Fetal Calf Serum or Bovin Serum Albumin.
The volume of CSF to be centrifuged depends on the cell count.
Number of nucleated cells per mm³ Procedure
> 600 2 drops of undiluted CSF (approx. 35 µL)

> 200 → ≤ 600 3 drops of undiluted CSF (approx. 55 µL)
> 30 → ≤ 200 7 drops of undiluted CSF (approx. 125 µL)
0 to ≤ 30 10 drops of undiluted CSF (approx. 180 µL)
1 drop = 18 µL and 14 drops = 250 µL

Spin at 600 RPM during 6 minutes or 1000 RPM during 5 minutes.
2.2. Staining
Let the slides dry for a few minutes.
Classical staining with May-Grünwald Giemsa or Wright.
When the smears were dried and before examining those under the microscope cover it with a cover glass.
2.3. Microscopy
Utilize the 10 X magnification for evaluating the cell count and the 100 X magnification for analyzing the
stained slides.
11.6 Gonadal involvement:
11.6.1 Definition of Testicular Involvement
Testicular involvement is defined as leukemic infiltration of the testis, documented by biopsy if the testis is the
only site of relapse.
11.6.2 Treatment of Testicular Involvement
- Patients with gonadal involvement can not be classified as VLR or AR low.

- The non-VHR patients with gonadal involvement are included in AR high risk group (see risk groups)
- VHR patients stay VHR.
- there is no local irradiation foreseen in the frontline treatment.

12 MRD guidelines
12.1 How to measure MRD?
• MRD is measured by Ig/TCR PCR (ASO-PCR or Genescan)
• In case MRD is not possible or failed by these technics, flow cytometry-based MRD can be
accepted.
12.2 When MRD measurements?
MRD to be performed for all patients after IA and after IB
• For VHR patients:
MRD to be tested after each block until BMT
• For non-VHR patients:
MRD at further timepoints performed only if MRDIB ≥10-4.

(However, if MRD after IA ≥10-2 and MRD after IB <10-4, control on a further point is
recommended)
12.3 Decisions taken from MRD results:

Decisional threshold:
• After IA:
If MRD after IA ≥10-2 : Patients initially VLR, AR1, or AR2: shift to VHR treatment
• After IB/B augm.
The level of decision is 10-3 :

12.4 Schematic overview

13 SCT Indications
13.1 Patient Selection for SCT

- Non CR after IA
- VHR patients with PPR and MRD ≥10-2 after IA
- MRD ≥10-3 after IB/IB Augmented
- Hypodiploidy <44 chromosomes
- Duplication of an hypodiploid clone (pseudo-tripoidy)
- MLL rearranged and PPR
- MLL rearranged and NCI HR criteria
Patients with high levels of minimal residual disease after IB/IB augmented (> 10-2) and after VANDA (>10-
3) should be treated in phase I/II protocols if available
13.2 Timing of SCT:

SCT must be performed after VANDA if the patient is in CR and as soon as the donor is available, with a
familial or unrelated donor.

13.3 Schematic Overview

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CLG Treatment guidelines for

Acute Lymphoblastic Leukemia

(to be used in paralel with the EORTC 58081 study)

• First Version – agreed after Ghent – 24/08/2010 – named :

1 RISK GROUP DEFINITIONS........................................................................................5

2 GENERAL SCHEME OF THE TREATMENT

3 IMPORTANT “MINOR” ADAPTATIONS AND

4 VERY LOW RISK (VLR) ....................................................................................................10

4.2 Protocol I A Reduced (Induction) - VLR ................................................................................................................................ 10

4.3 Protocol I B Reduced (Consolidation) - VLR ......................................................................................................................... 11

4.4 Interval therapy - VLR............................................................................................................................................................. 12

4.5 Protocol II Reduced – VLR (Reinduction or Late intensification) ....................................................................................... 13

4.6 Maintenance therapy - VLR .................................................................................................................................................... 13

5 AVERAGE RISK 1 (AR1) .................................................................................................14

5.2 Protocol I A (Induction) – AR1................................................................................................................................................ 14

5.3 Protocol I B (Consolidation) – AR1 ......................................................................................................................................... 15

5.4 Interval therapy – AR1............................................................................................................................................................. 16

5.5 Protocol II – AR1 (Reinduction or Late Intensification) ..................................................................................................... 17

5.6 Maintenance therapy – AR1 .................................................................................................................................................... 18

CLG_ALLFrontline_TreatmentGuidelines_vs03.02 data 21/11/2010 -1-

6.2 Protocol I A Augmented – AR2-B (Induction) ...................................................................................................................... 20

6.3 Protocol I B – AR2-B (Consolidation) ................................................................................................................................... 21

6.4 Interval therapy – AR2-B......................................................................................................................................................... 21

6.5 Protocol II - – AR2-B (Reinduction or Late intensification) ................................................................................................ 22

6.6 Maintenance therapy – AR2-B ............................................................................................................................................... 23

7 AVERAGE RISK 2 (AR2) - T-CELL ALL.................................................24

7.2 Procotol I A - AR2-T (Induction) .......................................................................................................................................... 25

7.3 Protocol I B - AR2-T (Consolidation)..................................................................................................................................... 25

7.4 Interval therapy - AR2-T......................................................................................................................................................... 26

7.5 Protocol II - AR2-T (Reinduction or Late intensification) ................................................................................................... 27

7.6 Maintenance therapy - AR2-T ................................................................................................................................................ 28

8 VERY HIGH RISK (VHR) ..................................................................................................29

8.2 Protocol I A – VHR (Induction).............................................................................................................................................. 30

8.3 Treatment of VHR patients beyond protocol IA.................................................................................................................... 30

8.4 Protocol I B augmented – VHR (1° Consolidation)............................................................................................................ 31

8.5 Protocol VANDA – VHR (2° Consolidation) ........................................................................................................................ 32

8.6 1° Interval therapy– VHR : 3 cures of HDMTX ................................................................................................................... 32

8.7 Protocol II modified – VHR ( 1° Reinduction or 1° Late Intensification).......................................................................... 33

8.8 2° Interval therapy – VHR: 3 cures of HDMTX ................................................................................................................. 34

8.9 Protocol II modified – VHR ( 2° Reinduction or 2° Late Intensification)............................................................................ 34

8.10 Maintenance therapy – VHR ................................................................................................................................................... 34

9 PRACTICAL GUIDELINES ...........................................................................................35

9.2 Induction (IA reduced, IA, IA augmented)............................................................................................................................. 35

9.3 Consolidation (IB reduced and IB).......................................................................................................................................... 37

CLG_ALLFrontline_TreatmentGuidelines_vs03.02 data 21/11/2010 -2-

9.5 Interval therapy ........................................................................................................................................................................ 37

9.6 Reinduction or Late Intensification (II reduced, II normal, II modified) ............................................................................ 39

9.7 2° Consolidation VHR ( VANDA) ........................................................................................................................................... 39

9.8 Maintenance .............................................................................................................................................................................. 40

10 GENERAL DRUG INFORMATION ................................................................42

10.2 Asparaginase (L-A’ase) ............................................................................................................................................................ 42

10.3 Cyclophosphamide (CPM) ....................................................................................................................................................... 42

10.4 Cytosine-arabinoside (ARA-C) ................................................................................................................................................ 43

10.5 Daunorubicin (DNR)................................................................................................................................................................. 43

10.6 Etoposide (VP-16) ..................................................................................................................................................................... 43

10.7 Corticosteroids .......................................................................................................................................................................... 43

10.8 Methotrexate (MTX)................................................................................................................................................................. 43

10.9 6-mercaptopurine (6-MP)......................................................................................................................................................... 43

10.10 6-thioguanine (6-TG) ............................................................................................................................................................ 43