Remarkable Activity of Bortezomib Combined with Chemotherapy in a Phase I Study of Relapsed Childhood Acute Lymphoblastic Leukemia (ALL). A Report from the Therapeutic Advances in Childhood Leukemia (TACL) Consortium.

The outcome of relapsed ALL remains very poor, and many re-induction regimens are highly toxic. We report here the Phase I component of a Phase I/II study of bortezomib added to 4-drug induction with vincristine, dexamethasone, pegylated asparaginase, and doxorubicin in children with relapsed ALL. A total of 10 patients were enrolled, 5 in 1^st marrow relapse (2 early and 3 late relapses) and 5 in 2^nd or subsequent relapse. Four patients were enrolled at dose level 1 (1 mg/m²) to obtain 3 evaluable patients. One patient was inevaluable for toxicity because of an error in dexamethasone doses and was removed after 8 days. No dose-limiting toxicity (DLT) was observed. Six patients were enrolled at dose level 2 (1.3 mg/m²), the standard single agent dose. One patient had a DLT (hypophosphatemia and rhabdomyolysis) after1 dose of bortezomib, and that patient died from diffuse zygomyces infection by day 17. Five additional patients were enrolled with no further DLT’s. As planned, no further dose escalation was pursued. The regimen had predictable toxicity related to the chemotherapy drugs. Only 2 patients had mild peripheral neuropathy (grades 1 and 2). Seven of the10 patients (70%) achieved a CR, and 1/10 had bone marrow CR with persistent central nervous system (CNS) leukemia despite weekly intrathecal (IT) methotrexate, for a total of 80% bone marrow CR rate. In conclusion: the combination of bortezomib with 4 standard drugs is highly active with acceptable toxicity in heavily pretreated relapsed pediatric ALL patients. We are expanding the MTD cohort for a phase II estimate, and intend to report updated results at the ASH meeting.