AIEOP-BFM ALL 2009

Progress in the treatment of acute lymphoblastic leukaemia in children and adolescents has been made in the last 10 to15 years mainly through refinement of risk stratification and adaptation of chemotherapy. New agents with proven benefit in the frontline therapy of ALL
have not been identified, therefore, chemotherapy could only be improved by more effective combination of existing agents. The advanced
knowledge about genetics of ALL and molecular regulation of treatment response and resistance represents the basis for the design of contemporary treatment protocols.

Study objectives

Primary Objectives

The primary aims of the AIEOP-BFM ALL 2009 study are to answer the following questions:

1. Non-HR pB-ALL patients with TEL/AML1-negative ALL or unknown TEL/AML1 status and FCM-MRD in bone marrow on day 15 < 0.1 % or with TEL/AML1-positive ALL (randomized study question): can the daunorubicin dose in Protocol IA be safely reduced by 50 % with a
non-inferior EFS and a reduction of toxicity (treatment-related mortality and AE/SAE in Protocol I)?

2. Patients with precursor-B ALL and risk group MR (randomized study question): can the clinical outcome be improved by protracted asparagine depletion achieved through application of intensified pegylated L-asparaginase during reintensification and early
maintenance?

3. High Risk patients (as identified by day 33 - randomized study question): can the clinical outcome be improved by protracted exposure to PEG-L-asparaginase during Protocol IB?

Secondary Objectives

The secondary goals of the AIEOP-BFM ALL 2009 study are to answer the following questions:

1. T-ALL non-HR patients: Can the high level of outcome (pEFS) which was obtained for these patients in study AIEOP-BFM ALL 2000 be preserved or even improved with the use of PEG-L-ASP instead of native E.coli L-ASP?

2. HR patients with persistingly high MRD levels despite the use of the HR blocks in the intensified consolidation phase “MRD Non-Responders”: Is it possible to improve the outcome and to achieve a further reduction of leukemic cell burden by administration of an innovative treatment schedule (DNX-FLA)? NOTE: if new drugs or therapeutic options become available, the experimental treatment
planned in this patient group may change during the course of the study.

3. SR patients identified by at least one sensitive marker: Is the clinical outcome comparable to that obtained in SR patients (identified with two sensitive markers) in AIEOP-BFM ALL 2000, or can the outcome even be improved with the use of PEG-L-asparaginase instead of native E. coli L-asparaginase?

4. What is the relative value of different methods of MRD monitoring in the definition of alternative stratification systems within a BFM-oriented protocol?

5. Patients participating in the randomized asparaginase studies (pB-ALL/MR, HR): Are asparaginase activity and asparaginase antibodies associated with development of allergic reactions, and do they have an effect on the outcome of the patients?

AIEOP-BFM ALL 2009 is a international, collaborative, prospective, randomized clinical trial and next to Germany participate Austria, Australia, Czech Republic, Israel, Italy and Suisse .

Basics of risk stratification

As in AIEOP-BFM ALL 2000, prednisone response, remission status on day 33, PCR-MRD and presence of MLL/AF4 are still used as stratification criteria in AIEOP-BFM ALL 2009 (BCR/ABL patients are to be treated in the EsPhALL study). In addition, patients are stratified
by immunophenotype (T-ALL or pB-ALL), presence of TEL/AML1, hypodiploidy, and according to MRD results on day 15 in bone marrow measured by flow cytometry. Patients with pB-ALL (or unknown immunophenotype) and PCR-MRD load of ≥ 10^-3 at Timepoint 1 and any positivity < 10^-3 at Timepoint 2 qualify for treatment in risk group HR (new PCR-MRD MR Slow Early Responder (SER) group).
In the case of non-availability of at least two sensitive MRD markers (sensitivity at least 10^-4), MRD risk group stratification can also be based on only one sensitive marker. However, the identification and use of at least two sensitive markers is still to be attempted.

Risk-groups

-T/non-HR: T-ALL in absence of any HR criteria (see below)

- pB/non-HR: pB-ALL in absence of any HR criteria (see below)

       Standard-risk:(PCR-MRD-SR or, if no PCR-MRD result available, FCM d15 < 0.1%)

        Medium-risk (no SR no HR)-

-High- risk: Prednisone poor-response, FCM ≥10% on day 15, non-remission on day 33, positivity for MLL/AF4 or t(4;11), hypodiploidy (< 45 chromosomes), high risk by PCR-MRD response

• newly diagnosed acute lymphoblastic leukaemia
• age ≥ 1 year4 (> 365 days) and < 18 years (up to 17 years and 365 days)
• no Ph+ (BCR/ABL or t(9;22)-positive) ALL5
• no evidence of pregnancy or lactation period
• no participation in another clinical study
• patient enrolled in participating center
• written informed consent

• pre-treatment with cytostatic drugs,
• steroid pre-treatment with ≥ 1 mg/kg/d for more than two weeks during the last month before diagnosis,
• treatment started according to another protocol,
• underlying diseases that prohibit treatment according to the protocol (e.g. severe congenital heart disease, Charcot-Marie Syndrome, Ataxia-teleangectasia…),
• ALL diagnosed as second malignancy.