Phase I Study of Ixazomib with Conventional Chemotherapy in the Treatment of Acute Myeloid Leukemia in Older Adults

Introduction: Outcome in acute myeloid leukemia (AML) for patients aged >60 years is poor with a median survival of approximately 11 months. Targeting the proteasome in AML is attractive, since leukemia stem cells demonstrate sensitivity to proteasome inhibition in preclinical models, perhaps through down regulation of nuclear NF-KB or MCL-1 through stabilizing effects on NOXA. AML cell lines are susceptible to synergistic cytotoxicity when bortezomib, a proteasome inhibitor, is combined with daunorubicin and cytarabine. We have shown that adding bortezomib to standard treatment in AML results in a high remission rate. A newer generation proteasome inhibitor, ixazomib, is less frequently associated with neurotoxicity, and, therefore, was selected for combination with conventional chemotherapy in this phase I trial. The primary objective of this study was to determine the recommended phase II dose (RP2D) of ixazomib in combination with intensive induction and consolidation chemotherapy for AML. A secondary objective was to determine if the level of CD74 in blasts correlated with response, since prior studies showed that CD74 may be a poor prognostic indicator, but its effect might be diminished with proteasome inhibition.

Methods: Adults >60 years of age with newly diagnosed AML were screened for eligibility. Patients with secondary AML were eligible, including those with prior hypomethylating agent (HMA) therapy for myelodysplastic syndromes (MDS). We excluded those with promyelocytic leukemia. There were 2 phases in this study. In the first phase (A), the induction treatment consisted of the following: cytarabine 100 mg/m2/day by continuous IV infusion, Days 1-7; daunorubicin 60 mg/m2/day IV, Days 1, 2, 3, and ixazomib was provided orally at the cohort dose, Days 2, 5, 9, and 12. Consolidation or transplant in this phase was at the discretion of the treating physician. In the second phase (B), induction was administered with the established RP2D of ixazomib in phase A. All patients were to be treated with the following consolidation: cytarabine at 2 g/m2/day, days 1-5 with ixazomib on days 2, 5, 9, and 12 at the cohort dose for consolidation.

A classical 3 + 3 patient cohort dose escalation design was used to determine whether the dose of ixazomib could be safely escalated in 3 cohorts (1.5 mg/day, 2.3 mg/day, 3.0 mg/day), initially in induction (phase A) and subsequently in consolidation (phase B). Secondary objectives included rate of complete remission (CR), disease-free survival (DFS), overall survival (OS), and outcome relationship with CD74.

Results: Thirty-nine patients were enrolled, including 15 (38%) patients with secondary AML, either with antecedent myeloid malignancy or therapy-related AML. Twenty-six patients (67%) were male, and the median age was 68 years (range 61-80 years). There were no grade 5 toxicities attributed to study drug. Four patients died before day 30 with persistent leukemia, 3 of whom were replaced for assessment of the MTD. Three other patients were not evaluable and were replaced. Nearly all grade 3 and 4 toxicities were hematologic (Table). There was 1 DLT (grade 4 platelet count decrease extending beyond Day 42). There were no grade 3 or 4 neurotoxicity events attributable to ixazomib. Among the 38 patients evaluable for response, 26 achieved CR, and 2 achieved CR with incomplete count recovery (CRi), for a composite remission rate (CCR) of 74%. Among the 15 patients with secondary AML, 9 achieved CR and 2 achieved CRi, for a CCR of 73%. The median OS for the 39 patients is 40.8 months [95% CI, 17.6, Inf]. The 18-month OS estimate was 63% [95% CI, 49-80%]. Of note, 30 patients underwent stem cell transplantation. There was no significant association between level of CD74 expression on blasts at baseline and response.

Conclusions: The highest dose level (3 mg) of ixazomib planned for induction and consolidation in this trial has been reached safely and is the recommended phase 2 dose for both. Notably, to date, no grade 3 or 4 neurotoxicity has been encountered. The remission rate for this regimen in this older adult population appears favorable. With ixazomib added in treatment, we saw no association of response rate with level of CD74 in blasts.

Amrein:Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Attar:Aprea: Current Employment. Brunner:Agios: Honoraria; Novartis: Consultancy, Research Funding; Acceleron: Honoraria; AstraZeneca: Research Funding; Celgene/BMS: Consultancy, Research Funding; GSK: Research Funding; Janssen: Research Funding; Keros Therapeutics: Consultancy; Taiho: Consultancy; Takeda: Consultancy, Research Funding; Aprea: Research Funding. Hobbs:Pharmaxis: Other: Advisor or review panel participant; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Advisor or review panel participant; Pfizer: Other: Advisor or review panel participant; Constellation: Membership on an entity's Board of Directors or advisory committees, Other: Advisor or review panel participant; PI, Research Funding; Keros: Other: Advisor or review panel participant; Bristol Myers Squibb Co./Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Advisor or review panel participant; Incyte: Other: Advisor or review panel participant; PI, Research Funding; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Advisor or review panel participant; Bayer: Research Funding; Merck: Research Funding. Neuberg:Madrigal Pharmaceuticals: Current equity holder in private company. Fathi:Novartis: Consultancy; Kite: Consultancy; Astellas: Consultancy; Forma: Consultancy; Orum: Consultancy; Abbvie/Servier: Consultancy, Other: Clinical Trial Support; Immunogen: Consultancy; Ipsen: Consultancy; AbbVie, Agios, Amgen, Astellas Pharma, Blueprint Medicines, Bristol Myers Squibb, Daiichi Sankyo, Foghorn Therapeutics, Forty Seven, Inc., Genentech, Ipsen, Kite Pharma, Kura Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Foghorn: Consultancy; EnClear: Consultancy; Mablytics: Consultancy; Morphosys: Consultancy; AbbVie, Agios, Bristol Myers Squibb, Servier, and Takeda: Research Funding; PureTech: Consultancy; Celgene/BMS: Consultancy, Other: Clinical Trial Support; Amgen: Consultancy; MorphoSys, Novartis, Pfizer, Seattle Genetics, Takeda, Trillium Therapeutics, and Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy.

ixazomib: this proteasome inhibitor may improved the effectiveness of standard chemotherapy in the treatment of AML.