Phase I Study of Ixazomib in Addition to Chemotherapy for the Treatment of Acute Lymphoblastic Leukemia in Older Adults

Introduction: While progress has been made in the treatment of childhood leukemia, the outlook for patients >60 years of age with acute lymphoblastic leukemia (ALL) is poor with complete remission rates of approximately 60% and 3-year survivals of less than 15% (Larson R., Hematology 2005). Ixazomib is an oral proteasome inhibitor, which has shown single agent activity and promising combination activity in pediatric ALL patients (Messinger, Blood 2012). We sought to assess the safety and tolerability, as well as an early appreciation of the therapeutic promise, of adding ixazomib to standard multi-agent standard treatment for older adults with ALL.

Methods: Patients aged 51 to 75 years of age with newly diagnosed B-ALL and T-ALL were screened for eligibility. Excluded were patients with mature ALL (including Burkitt's). Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible and tyrosine kinase inhibitor therapy was added to the chemotherapy on Day 10 for these patients. The induction treatment consisted of the following:

Prednisone 40 mg/m2/day, Days 2-22 for patients <60 years of age;

Prednisone 40mg/m2/day Days 2-8 for patients ≥ 60 years of age;

Vincristine (V) 2 mg IV on Days 2, 9, 16, 23;

Doxorubicin (D) 30mg/m2/day on Days 2 and 3; intrathecal cytarabine 50 mg on Day 2;

Intrathecal methotrexate 12 mg Day 29;

G-CSF 300 mcg/kg sc or IV was started on Day 5 and continued until ANC was >2000 for 2 consecutive days. On Days 1, 8, 15, ixazomib was given orally at the dose prescribed according to 3 dose-escalation cohorts: 2.3 mg/day, 3.0mg/day, or 4.0 mg/day.

A standard 3 +3 patient cohort dose escalation design was used to determine the dose of ixazomib for each patient. The primary objective of the study was to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients.

After induction patients received consolidation I consisting of the following: cyclophosphamide 750 mg/m2/day, Days 2-3; prednisone 40 mg/m2/day, Days 2-6; PEG-asparaginase 500 units/m2 IV on Day 2 (for Ph- patients only); intrathecal methotrexate 12 mg on Days 2 and 15.

On Days 1, 8, 15 of consolidation I, ixazomib was given orally at the dose previously prescribed for them during induction. After consolidation I, patients in complete remission (CR) with a suitable donor were offered stem cell transplantation as per institutional guidelines. Those not going to transplantation proceeded to continuation therapy as follows:

CNS Phase: Intrathecal methotrexate 12 mg, cytarabine 40 mg, hydrocortisone 50 mg on days 1, 8, 15, vincristine Day 1, doxorubicin on Day 1, 6-MP Days 1-14, dexamethasone (DEX) Days 1-5, PEG-ASP Day 1+15

Consolidation II: 8 cycles of V + D + 6-MP + DEX + PEG-ASP;

Maintenance Phase: V + DEX + 6+MP + oral methotrexate (ends after 18 months of remission).

Results: The dose escalation phase completed with 9 patients. Among these patients, 4 harbored BCR-ABL1 rearrangements, all had B-ALL, the median age was 65 years, 78% were male, and 78% were performance status 1. The MTD was 2.3 mg of ixazomib, as 2 patients at 3.0 mg developed DLT's, a grade 3 peripheral neuropathy and a grade 5 acute kidney injury. Grade 3 and 4 toxicities included grade 4 neutropenia in 8 patients and grade 4 thrombocytopenia in 7 patients. Two patients experienced grade 3 thrombocytopenia. There was 1 patient with a grade 2 neuropathy that did not meet the definition of DLT. Among the 9 patients, 7 (78%) achieved CR, and 2 patients went on to stem cell transplantation.

Conclusions: A dose of 2.3 mg of ixazomib was well-tolerated in combination with induction chemotherapy among older patients with ALL, and is being tested in the expansion phase of this trial. The remission rate in this older adult population appears favorable in both Ph-negative and Ph-positive patients.

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