Bortezomib Combined with Mitoxantrone, Vincristine, Peg-Asparaginase and Dexamethasone for Children with Relapsed Acute Lymphoblastic Leukemia

Introduction: Outcomes for children or adolescents with relapsed or refractory acute lymphoblastic leukemia (ALL) are poor, especially for those who experience a second or greater relapse. Novel treatments are needed, however the addition of newer medications to standard therapy is problematic due to the risk of additional toxicities in this high risk population. Mitoxantrone was shown to be superior to idarubicin for patients with a first ALL relapse when combined with vincristine, PEG-asparaginase and dexamethasone and is now frequently used in the treatment of relapsed ALL. Bortezomib is a proteasome inhibitor that has shown activity in relapsed ALL when given in combination with reinduction chemotherapy including doxorubicin. This study evaluates the addition of bortezomib to a reinduction regimen that includes mitoxantrone, dexamethasone, vincristine and PEG-asparaginase for children with relapsed or refractory ALL.

Methods: Children ages 0-18 who had experienced one or more relapse of ALL were included in the analysis. Treatment included bortezomib 1.3 mg/m²/dose IV on days 1, 4, 8 and 11, dexamethasone 10 mg/m²/dose PO BID on days 1-5 and 15-19, mitoxantrone 10 mg/m²/dose IV on days 1 and 2, PEG-asparaginase 2500 units/m²/dose on days 3 and 17, vincristine 1.5 mg/m²/dose (max dose: 2 mg) IV on days 1, 8, 15 and 22 and intrathecal methotrexate (standard age based dosing) on days 1 and 8. Erwinase was used for patients with hypersensitivity to PEG-asparaginase and triple intrathecal chemotherapy with hydrocortisone, cytarabine and methotrexate was allowed for patients with active CNS disease. It was recommended that all patients remain hospitalized until count recovery and that all patients receive prophylactic broad-spectrum antibiotic and antifungal prophylaxis while neutropenic.

Results: The treatment was administered to 10 children, ages ranging from 11 months to 18 years. Nine patients had precursor B-cell ALL and 1 had T-cell ALL. Nine patients had bone marrow disease and one patient had extramedullary disease in the parotid and submandibular glands along with bone marrow MRD. Patients had between 1 and 4 (median: 2) prior remissions, 2 patients were refractory to their previous therapy and 5 patients had received a prior allogeneic hematopoietic stem cell transplant. There was 1 treatment related death from a presumed pulmonary fungal infection. Of the 9 patients that had a post therapy evaluation, 8 (89%) were in complete remission with less than 5% blasts and 2 (22%) were MRD negative by flow cytometry. One patient was in remission but MRD positive after treatment, declined any further therapy, became MRD negative and maintained a complete remission for 7 months before eventually experiencing a relapse. Of the children that responded to treatment, 2 remain in remission at 2 and 14 months from the completion of therapy and 6 patients have had at least one relapse. Including all patients that were treated, 8 (80%) remain alive with a median follow-up of 21 months. Grade 3 or higher infections were noted in 7 (70%) patients and 2 patients required PICU admission and ventilator support. Two patients had grade 4 pulmonary toxicity, one associated with MRSA sepsis and the other of unclear etiology 25 days following the last bortezomib dose. No patient had ≥ grade 2 neurotoxicity associated with treatment. Event free and overall survival of this cohort at 12 months were 35% and 79%, respectively.

Conclusions: The addition of bortezomib to intensive multiagent reinduction chemotherapy including mitoxantrone was feasible and did not result in unexpected toxicity in a heavily pretreated patient cohort. The combination treatment resulted in complete morphologic remission for the majority of patients. The incorporation of bortezomib with reinduction chemotherapy including mitoxantrone warrants further evaluation in the treatment of relapsed ALL in children.