International Study for Treatment of High Risk Childhood Relapsed ALL

Although survival of children with acute lymphoblastic leukemia (ALL) has considerably improved over the past few decades, relapsed ALL remains a leading cause of mortality in children with cancer. Risk has been defined by the International BFM Study Group (I-BFM-SG) based on duration of first remission, immunophenotype of malignant clone, and site of relapse. Patients classified as high risk (HR) by these criteria have poor response rates to standard induction therapy, high rates of subsequent relapse and require an allogeneic hematopoetic stem cell transplantation (allo-HSCT) for consolidation of 2nd remission. Over the last decade members of the I-BFM-SG have investigated the use of different combinations of conventional cytotoxic agents. Even with allo-HSCT, none of these approaches have improved outcome above 40%. Therefore, for HR patients there is a need to investigate the curative potential of new agents combined with systemic therapy.



The proteasome inhibitor bortezomib has shown synergistic activity with acceptable toxicity when combined with corticosteroids, anthracyclines and alkylating agents in adult patients with cancer as well as with dexamethasone, doxorubicin, vincristine and PEG-asparaginase in children with refractory or relapsed ALL. In the I-BFM-SG IntReALL HR 2010 study, the potential of Bortezomib combined with a modified ALL R3 backbone as induction regimen for HR patients to improve CR2 rates will be investigated in a randomized phase II design. Induction is followed by conventional intensive consolidation.

Primary objectives:

Improvement of CR2 rates after induction with ALL R3 with bortezomib versus without bortezomib in HR relapsed ALL patients



Secondary objectives:

Improvement of Event Free Survival (EFS) and overall survival (OS) rates

Improvement of minimal residual disease (MRD) reduction after induction with versus without bortezomib

Improvement of MRD load prior to SCT

Increasing the proportion of HR patients reaching SCT

Prognostic relevance of MRD pre SCT

Improvement of CR2 and/or MRD rates during consolidation

Toxicity of induction with versus without bortezomib

The IntReALL HR 2010 trial is an inter-group, international multi-centre, treatment optimization

trial. It contains the following treatment arms:

- induction: prospective, randomized, adaptive, open label phase II trial comparing arm A

(modified ALL R3) versus arm B (modified ALL R3 + bortezomib).

- post-induction single arm observational trial with intensive multidrug chemotherapy courses

HC1 (modified AIEOP-BFM ALL 2009 HR1), HC2 (modified HR3)

- a third post-induction chemotherapy block HC3 (modified AIEOP-BFM ALL HR2) may

optionally be given within the IntReALL HR 2010 trial or used as standard comparator for an

investigational window trial

- all patients in morphological CR2 will be subjected to allogeneic HSCT

- termination of the trial after completion of the 2nd or 3rd consolidation block before investigational window trial and/or allogeneic HSCT. Follow-up will be done until reaching

secondary EFS / OS endpoints.

- patients with insufficient treatment response (MRD ≥ 10-3 after induction) may be allocated to

individualized consolidation therapy based on individual biologic features of the leukemia, if such approaches are available

Bortezomib (Velcade)

Participation in the trial does not result in additional investigations as compared to the standard treatment of children with relapsed ALL.



The risk of increased toxicity by adding Bortezomib to the standard ALL-R3 remission induction is considered to be low and will be closesly monitored by the pharmacovigilance system established within the IntReALL group. Strict stopping rules apply. The induction randomization implies realistic potential to improve remission, EFS and at the end cure rates in this unfavourable patient group with an acceptable and closely monitored risk for increased toxicity.