Interfant 06

Primary objective:
1. To assess the role of an early intensification of two "AML" induction blocks versus protocol Ib directly after induction, in a randomized way in MR and HR patients.

Secondary objectives
1. To assess the role of an early intensification of two "AML" induction blocks versus protocol Ib directly after induction, in a randomized way in MR and HR patients, separately.
2. To assess the overall outcome of the Interfant-06 protocol compared to the historical control series, especially the Interfant-99.
3. To assess the outcome of LR, MR and HR patients as compared to the historical control series in Interfant-99.
4. To study which factors have independent prognostic value.
5. To assess the role of SCT in HR patients and MR patients with MRD levels of ≥ 10e-4 at the start of OCTADA(D).

Stratification into 3 risk groups Low risk (LR), Medium Risk (MR) and High risk (HR), will be based upon the MLL status, age and WBC/prednisone response. The LR group will consist of all MLL germline cases, including MLL germline patients with a PPR. Determining the MLL status by split signal FISH in Interfant-06 will be mandatory for participating groups.

Criteria for HR patients are those:
1. who are MLL rearranged,
2. and < 6 months and
3 . have either a WBC ≥ 300 or a prednisone poor response.
MR patients are all others.

All low risk patients receive the standard arm. There is no randomization in the Low risk group.
Medium risk and high risk patients are randomised to receive the standard or experimental arm.
The outcome of MR and especially HR patients needs to be improved. Therefore, in these patients a randomised question will be asked whether two blocks of AML induction chemotherapy will improve outcome. AML blocks are used because infant MLL has myeloid characteristics. The AML blocks are well tolerated by infants with AML (Webb 2001). The courses that will be randomised will be
introduced early, after induction, because early relapse is still the major problem in treatment of infant ALL.
Because of the cumulative dose of anthracyclines in the experimental arm, OCTADAD will be without anthracyclines (called OCTADA) in this latter arm.

HR patients will follow the same protocol and randomisation as MR patients.
The only difference is that they will be eligible for allogenic SCT whereas MR patients are eligible for SCT only if they have a MRD level ≥ 10^-4 at TP5. Time of SCT will be after MARMA so before OCTADA(D) or during OCTADA(D). Donor selection, conditioning regimen and graft versus host prophylaxis will be performed as advised by Christina Peters (ALL-SZT 2003).

• Children aged 365 days or less with newly diagnosed acute lymphoblastic leukemia (ALL) or biphenotypic leukemia according to EGIL criteria. Children with CNS or testicular leukemia at diagnosis are eligible. It is important that all infants with ALL less than 1 year of age, including those infants who are eligible but are not treated according to the protocol are registered so that any selection bias can be determined
• Morphological verification of the diagnosis, confirmed with cytochemistry and immunophenotyping. In case a bone marrow aspiration results in a “dry tap”, a trephine biopsy is advised unless it is possible to confirm the diagnosis by peripheral blood examination.
• Informed consent of the parents or other legally authorized guardian of the patient.

• Mature B-ALL, defined by the immunophenotypical presence of surface immunoglobulines or t(8;14) and breakpoint as in B-ALL.
• The presence of the t(9;22) (q34;q11) or bcr-abl fusion in the leukemic cells (if these data are not known, the patient is eligible).
• Age > 365 days
• Relapsed ALL
• Systemic use of corticosteroids less than 4 weeks before diagnosis. Patients who received corticosteroids by aerosol are eligible for the study.