EsPhALL2017 / COGAALL1631

Ca. 3-5 % of the cases with ALL in children and adolescents are characterized with the evidence of the Philadelphia-Chromosome (translocation t(9;22), molekular equivalence: BCR-ABL-fusion). Since the introduction of tyrosine kinase inhibitors in the treatment of Ph+ patients, more than half of the patients can be healed withou HSCT. But historically european as well as american studies used high intensive chemotherapies with severe the side effects. The reduction of these adverse events despite an acceptable relapse rate would be an important progress in the treatment of this children and adolescents.

Primary objectives

• SR-Randomization: To compare disease-free survival (DFS) of Standard Risk (SR) Ph+ ALL patients treated with continuous imatinib (TKI) combined with either the EsPhALL chemotherapy backbone (Arm A) or a less intensive a high-risk COG ALL chemotherapy backbone (Arm B), according to the randomization result.

Secondary objectices

• To compare disease free survival (DFS) of SR Ph+ and ABL-class fusion positive ALL patients treated with Arm A vs. Arm B.
• To determine the feasibility of administration of imatinib after allogeneic HSCT in High Risk (HR) Ph+ ALL patients.
• To determine event-free-survival (EFS) of HR pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission and post-HSCT imatinib.
• To compare rates of Grade 3 or higher infections in SR Ph+ ALL patients between the two randomized arms.

Stratification:
Ph+ ALL patients will enter the trial at Day 15 of Induction IA and begin daily imatinib at that time. ABL-class fusion positive ALL patients will enter the trial at the start of Induction IB phase and begin daily imatinib at that time. After the Induction IB phase (week 10-12), MRD will be assessed by immunoglubulin-T-cell-receptor (IgH-TCR) PCR, and patients will be classified as SR (those with MRD < 5 x 10-4) or High Risk (HR; MRD > 5 x 10-4).

Therapy:
SR patients will be randomized to receive one of two cytotoxic chemotherapy backbones: 1) the EsPhALL backbone (Arm A) used in previous EsPhALL protocols and COG AALL1122/CA180372 or 2) a less intensive regimen similar to those typically administered to non-Ph+ ALL HR patients on COG trials (Arm B). Patients on both arms will continue to receive imatinib until the completion of all planned chemotherapy (two years of treatment).

High-risk patients: HR patients (approximately 15-20% of patients), allogeneic HSCT in CR1 is still considered the treatment of choice. On EsPhALL 2017/COG AALL1631, HR patients will receive the EsPhALL chemotherapy backbone and proceed to HSCT after completion of the three consolidation blocks.
Because there is variability in clinical practice regarding the use of TKI’s post-HSCT in Ph+ and ABL-class fusion positive ALL, and controversy regarding their impact on toxicity, graft-versus-host disease (GVHD) and Event Free Survival (EFS), the feasibility and describe the outcome of post-HSCT imatinib administration will be tested. Imatinib will be administered to all HR patients from Day +56 until Day +365 post-HSCT. This single-arm, Phase 3 study will be the largest prospective trial of a pediatric population uniformly treated with imatinib pre- and post-HSCT.

• Children and adolescents aged 1-17 years at diagnosis, with documented by either cytogenetics, PCR or FISH for bcr-abl
• Eligible for the current local prospective therapeutic study of childhood ALL
• Informed consent was given by the parents or by legal guardian.

• Abnormal hepatic function (ALAT/ASAT >10 times the upper limit of the normal range)
• Abnormal renal function (creatinine >1.5 times the upper limit of the normal range or a calculated creatinine clearance of 80 ml/
• Active systemic bacterial, fungal or viral infection as documented by positive cultures, radiological imaging techniques, septic shock symptoms.