Minimal Toxicity of Imatinib Mesylate in Combination with Intensive Chemotherapy for Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) in Children: A Report of the Children’s Oncology Group (COG) AALL0031 Protocol for Very High Risk ALL.

We tested whether imatinib mesylate, the first Bcr/Abl tyrosine kinase inhibitor, can be given safely in combination with chemotherapy for children with Ph+ ALL in an effort to improve outcome. Imatinib alone has a number of known side effects, including peripheral edema as well as cardiac and hepatic toxicities. Little is known about toxicities that may occur when imatinib is given with different chemotherapeutic agents, particularly in high dosages and in children. The COG study, AALL0031, evaluated whether imatinib mesylate could be administered in conjunction with chemotherapy in children (1–21 years) with Ph+ ALL. AALL0031 accrued 160 very high risk ALL patients (Ph+, induction failure, hypodiploidy, MLL with slow early response) from 10/02 to 5/06, including 94 Ph+ ALL patients eligible to receive imatinib. Patients entered the study after induction and received an intensive multidrug chemotherapy backbone with stepwise introduction of imatinib (340 mg/m2/day for 21 days) into an increasing number of treatment blocks in the first 4 cohorts (44 pts), followed by continuous dosing in the final patient cohort (50 pts). Patients that had an HLA-identical family donor underwent hematopoietic stem cell transplantation (HSCT) after the first 2 cycles of therapy. A number of patients received identical chemotherapy without imatinib, including different blocks of therapy within Ph+ ALL cohorts 1–3 (32 pts) and 66 Ph-neg pts, allowing for an evaluation of the impact of imatinib on a common chemotherapy backbone. Targeted toxicities were hemorrhage, hepatic toxicities (bilirubin, AST, ALT) and coagulation abnormalities (PTT and PT). Patients receiving imatinib had a higher incidence of ALT elevation (but not bilirubin or AST) in Consolidation 1 (10/65 versus 4/69; p = 0.07), Maintenance cycle 2 (6/23 versus 0/16; p = 0.06) and maintenance cycle 6 (8/12 versus 0/7; p = 0.01). Maintenance was the first time that 6-MP and imatinib were given together. An amendment shortening imatinib dosing from 21 to 14 days duration in maintenance cycles 5 – 12 resulted in a significant decrease in ALT grade >=3 toxicity from 54% (17/31) to 28% (11/40) (p = 0.01) as well as for AST (p = 0.02) but not bilirubin (p = 0.11). Additional toxicity comparisons (hemoglobin, neutropenia, platelets) in selected phases showed no differences between patients receiving imatinib versus no imatinib. Patients receiving imatinib had fewer RBC transfusions in consolidation 1 than the no Imatinib group (p = 0.0008). Patients receiving imatinib had a significantly lower incidence of infection with grade 3/4 neutropenia in intensification 1 (0/29) compared to patients not receiving imatinib (16%, 7/48, p = 0.04) with a similar trend in intensification 2 (p = 0.06). Intensification 1 and 2 contain methotrexate, etoposide, cyclophosphamide, cytarabine and L-asparaginase. In conclusion, imatinib mesylate at 340 mg/m2 given in a continuous dosing schedule can be used in combination with very intensive chemotherapy blocks with no additional toxicity in children with Ph+ ALL.