Proteasome inhibitors (PIs) capitalize on the constitutive activation of NF-KB in AML cells and increase chemosensitivity to anthracyclines and cytarabine. We combined the second generation PI, ixazomib, with the AML salvage regimen MEC (mitoxantrone, etoposide, cytarabine) in patients (pts) with relapsed/ refractory (R/R) AML. The maximum tolerated dose (MTD) of ixazomib was 1.0 mg (ASH 2016, Abstract 4065). Here, we present the final efficacy results and the association of gene expression (expn) profiling with response.
Methods: Pts were treated at Cleveland Clinic and University Hospitals of Cleveland from Oct 2014 to Jan 2017. An IND was approved by the FDA, and the protocol was approved by each review board. Eligibility: age 18-70 yrs, R/R AML, and cardiac ejection fraction ≥ 45%. Samples were stored for gene expn pre- and post-treatment (tx) (at the time of response assessment). Pts received MEC: M (8 mg/ m2), E (80 mg/m2), C (1000 mg/m2) intravenous Days 1-6. Ixazomib (Millenium; Cambridge, MA) was given orally on Days 1, 4, 8, and 11 and was escalated using a standard 3x3 design. Dose levels (DLs): 1 (1.0 mg), 2 (2.0 mg), 3 (3.0 mg). An additional 18 pts were treated at the MTD. One cycle of tx was administered. Response was assessed by bone marrow aspirate by Day 45 and complete remission (CR) was defined by IWG criteria. Toxicities were graded using CTCAE v 4.03. Gene expn profiling: whole-transcriptome analysis was performed using the TruSeq stranded total RNA library prep kit with Ribo-Zero (Illumina). Differential genes were identified by a cut-off of FDR < 0.05. GenePattern was used to perform enrichment analysis to identify differentially represented pathways.
Results: 30 pts were enrolled: 27 (DL1); 3 (DL2). The median age was 58 yrs (range 31-70), 16 (53%) were male and the median baseline WBC was 1.79 K/ uL (range 0.1-35.55). The median time from initial diagnosis to registration was 7.6 months (mos) and 8 pts (27%) had a history of an antecedent hematologic disorder. Fourteen pts were in 1st relapse; 13 pts were refractory to their last tx. Two pts had received a prior allogeneic hematopoietic cell transplant (AHCT), 7 pts had FLT3 ITD mutations, and 7/ 29 pts (24%) had adverse cytogenetics per CALGB 8461 criteria. Grade 3-5 non-hematologic toxicities (≥ 15% of pts) included: infection (74%), febrile neutropenia (85%), hypotension (18%), hypoxia (19%), and mucositis (15%). The overall response rate was 53% [CR/ CR with incomplete count recovery (CRi)] [11 CRs/ 5 CRis] with a 10% early mortality rate. Thirteen pts proceeded to AHCT and 1 pt received a donor lymphocyte infusion. Seven of these 14 pts remain alive (median follow-up of 14.5 mos). The number of mutations in DNTMT3A, TP53, ASXL1, and NRAS (0, 1, >1) is associated with a worse response to salvage therapy (Abstract 3825, ASH 2015). Ten of 21 pts with available data had at least 1 of these mutations and 8/10 achieved CR/ CRi. To identify a signature predictive of response to tx, we performed RNASeq analysis on 17 pts pre-tx and 11 pts post-tx. Genes were differentially expressed between resistant and responding pts in: 314 genes (pre-tx), 217 genes (after-tx), and 72 genes (at both time points). Gene set enrichment analysis was conducted by comparing genes at baseline in responding versus resistant pts and identified significantly differentially expressed genes clustering in heme-metabolism and erythroblast differentiation, inflammatory response (interferon γ and α, TNFα), cytokine/ STAT signalling (IL2/ STAT5 and IL6/JAK/STAT3), NF-KB, and hypoxia. Using exact logistic regression and linear discriminant analysis, we identified 2 genes [IFI30 (γ-interferon-inducible lyosomal thiol reductase, GILT)] and [RORα (retinoic acid-related orphan receptor A] which were significantly different between responding and resistant pts and could classify CR if: 0.2012*RORα - 0.0215*IFI30 was > 0.1. IFI30, which may increase the levels of anti-oxidants and lead to a decreased ER stress- response to tx, was more highly expressed in resistant pts. RORα, a tumor suppressor gene, was down regulated in resistant pts
Conclusions: The combination of MEC and ixazomib was well-tolerated and effective in R/R AML. Results from gene expn profiling may help identify resistant pts and provide further therapeutic targets. In vitro studies are planned to clarify whether the use of RORα agonists may help sensitize resistant cells to tx.
Advani: Takeda/ Millenium: Research Funding; Pfizer: Consultancy. Cooper: Novartis: Research Funding. Carew: Millenium/ Takeda: Research Funding. Gerds: CTI BioPharma: Consultancy; Incyte: Consultancy. Caimi: Seattle Genetics: Equity Ownership; Incyte: Equity Ownership; Abbvie: Equity Ownership; Celgene: Speakers Bureau. Malek: Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Little: Hemex Health: Equity Ownership. Maciejewski: Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fees; Ra Pharma: Consultancy. De Lima: Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Research Funding. Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees.
Asterisk with author names denotes non-ASH members.
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