In:
Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4065-4065
Kurzfassung:
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 standard AML salvage regimen of MEC (mitoxantrone, etoposide, cytarabine). The primary objectives of this study were to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and phase 2 dose of ixazomib in combination with MEC in relapsed/ refractory (R/R) AML. Secondary objectives included evaluating the efficacy of this combination and correlating response to the gene expression profile and CD74 expression, which may identify a subset of leukemias in which NF-KB is operative with increased sensitivity to PI (Attar et al. CCR 2008; 14: 1446-54). Methods: Patients (pts) were treated at Cleveland Clinic and University Hospitals of Cleveland from Oct 2014 to present. An IND was approved by the FDA, and the protocol was approved by each institutional review board. Eligibility: age 18-70 yrs, R/R AML, and cardiac ejection fraction ≥ 45%. The fraction of blasts positive for CD74 was assessed by flow cytometry. Samples were stored for gene expression profiling pre- and post-treatment (at the time of response assessment). Pts received MEC: mitoxantrone (8 mg/ m2), etoposide (80 mg/m2), and cytarabine (1000 mg/m2) intravenous (IV) Days 1-6. Ixazomib, provided by Takeda, was given orally on Days 1, 4, 8, and 11 and was dose escalated using a standard 3x3 design. Dose levels (DLs): 1 (1.0 mg), 2 (2.0 mg), 3 (3.0 mg), 4 (3.7 mg). An additional 18 pts were to be treated at the MTD. One cycle of treatment was administered. Response was assessed by bone marrow aspirate/ biopsy by Day 45 and complete remission (CR) was defined by IWG criteria (Cheson 2006). Toxicities were graded according to NCI CTCAE v 4.03. Toxicities secondary to neutropenia or sepsis were not considered DLTs. DLTs included: (1) ≥ Grade 4 non-hematologic toxicity (NHT) with the exception of nausea, vomiting/ alopecia and drug-related fevers; (2) any ≥ Grade 3 neurologic toxicity; (3) grade 4 platelet or neutrophil count 50 days beyond the start of chemotherapy and not related to leukemia; (4) any Grade 4 NHT 〉 grade 2 by 45 days beyond the start of chemotherapy. Grade 2, 3, and 4 hyperbilirubinemia were redefined as 1.5- 〈 10x upper limits of normal (ULN), 10-20 x ULN, and 〉 20 x ULN. Results: Of 23 pts enrolled, 22 are evaluable. The median age was 58 yrs (range 31-70), 12 (52%) were male and the median baseline WBC was 2.56 K/ uL (range 0.1-62.9). The median time from initial diagnosis to registration was 7.1 months (range 1.4-36.8) and 7 pts (30%) had a history of an antecedent hematologic disorder. Thirteen pts were in 1st relapse and 10 pts were refractory to their last therapy. One pt had received a prior allogeneic hematopoietic cell transplant (AHCT), 7 pts had FLT3 ITD mutations and 7/ 21 pts (33%) had adverse cytogenetics per CALGB 8461 criteria at the time of relapse. At DL1, 1 DLT occurred (grade 4 thrombocytopenia), so this DL was expanded to 6 pts. At DL2, 2 pts developed Grade 4 thrombocytopenia; therefore, the MTD of ixazomib was 1.0 mg. The most common grade 3-5 NHTs in the dose escalation phase were febrile neutropenia (100%), hypoalbuminemia (25%), hypokalemia (42%), hypotension (33%), and respiratory failure (33%). No adverse events in the dose escalation phase were attributed to ixazomib alone. The overall response rate was 55% [CR/ CR with incomplete count recovery (CRi)], and 9 pts proceeded to AHCT. Five of these 9 pts remain alive with a median follow-up of 12.8 months. Five pts had CD74 expression performed. Two pts had high levels of CD74 expression ( 〉 80%); and both achieved CRi. Myeloid mutation panel data was available in 14 pts. Previous data has demonstrated the number of mutations in DNTMT3A, TP53, ASXL1, and NRAS (0, 1, 〉 1) is associated with a worse response to salvage therapy (Advani et al, abstract 3825, ASH 2015). Seven pts had at least one of these mutations and 6 of the 7 achieved CR/ CRi. Conclusions: The combination of MEC and ixazomib was well-tolerated and produced an overall response rate of 55% in patients with relapsed/ refractory AML irrespective of molecular mutation status. The combination is safe with a similar toxicity profile to MEC alone. CD74 expression may represent a biomarker for response to this therapy. Results from gene expression profiling will be complete by the time of the meeting and will be presented. Disclosures Mukherjee: Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Caimi:Genentech: Speakers Bureau; Gilead: Consultancy; Roche: Research Funding; Novartis: Consultancy. Maciejewski:Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Speakers Bureau. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.
Materialart:
Online-Ressource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V128.22.4065.4065
Sprache:
Englisch
Verlag:
American Society of Hematology
Publikationsdatum:
2016
ZDB Id:
1468538-3
ZDB Id:
80069-7
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