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A Phase 1 Study of Azacitidine with High-Dose Cytarabine and Mitoxantrone in High-Risk Acute Myeloid Leukemia

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A Phase 1 Study of Azacitidine with High-Dose Cytarabine and Mitoxantrone in High-Risk Acute Myeloid Leukemia REGULAR ARTICLE A phase 1 study of azacitidine with high-dose cytarabine and mitoxantrone in high-risk acute myeloid leukemia Downloaded from https://ashpublications.org/bloodadvances/article-pdf/4/4/599/1715665/advancesadv2019000795.pdf by UNIVERSITY OF CHICAGO LIBRARY user on 04 March 2020 Kirk E. Cahill,1,* Yasmin H. Karimi,1,* Theodore G. Karrison,2,3 Nitin Jain,4 Margaret Green,4 Howard Weiner,4 Noreen Fulton,4 Sabah Kadri,5 Lucy A. Godley,3,4 Andrew S. Artz,3,4 Hongtao Liu,3,4 Michael J. Thirman,3,4 Michelle M. Le Beau,3,4 Megan E. McNerney,3,5 Jeremy Segal,3,5 Richard A. Larson,3,4 Wendy Stock,3,4 and Olatoyosi Odenike3,4 1Department of Medicine, University of Chicago Medicine, Chicago, IL; 2Department of Public Health Sciences, University of Chicago, Chicago, IL; and 3Comprehensive Cancer Center, 4Section of Hematology/Oncology, Department of Medicine, and 5Department of Pathology, University of Chicago Medicine, Chicago, IL In this phase 1 study, azacitidine (AZA) was given before high-dose cytarabine (HiDAC) Key Points and mitoxantrone (mito) based on the hypothesis that epigenetic priming with • The recommended a hypomethylating agent before cytotoxic chemotherapy would improve response rates in phase 2 dose of AZA patients with high-risk acute myeloid leukemia (AML), including relapsed/refractory is 75 mg/m2 per day disease. The primary objective was to establish the recommended phase 2 dose of AZA given on days 1 to 5 followed before standard HiDAC/mito. In a dose escalation scheme, 46 patients (median age, 66 years) by HiDAC/mito once received AZA at 37.5, 50, or 75 mg/m2 subcutaneously or IV once daily on days 1 to 5 followed each on days 6 and 10. by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10 (the • High responses oc- HiDAC/mito dose was reduced 33% in elderly subjects). Two dose-limiting toxicities occurred curred in treatment- (both in the same patient): acute liver failure and kidney injury at the 50 mg/m2 dose. The naive patients aged 30-day induction death rate was 2.2% (1 of 46). The overall response rate, including complete $60 years with de novo remission and complete remission with incomplete count recovery, was 61% (28 of 46). or therapy-related AML $ and those with NPM1 Previously untreated patients aged 60 years with therapy-related AML and de novo AML or IDH2 mutations. were more likely to respond than untreated patients with AML progressing from an antecedent hematologic disorder (myelodysplastic syndrome and chronic myelomonocytic leukemia). Patients with favorable European Leukemia Network risk (P 5 .008), NPM1 mutations (P 5 .007), or IDH2 mutations (P 5 .03) were more likely to respond, and those with TP53 mutations (P 5 .03) were less likely to respond. The recommended phase 2 dose of AZA is 75 mg/m2 per day on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10. This trial was registered at www.clinicaltrials.gov as #NCT01839240. Introduction Acute myeloid leukemia (AML) has a poor prognosis overall, with a 5-year survival of ;27%.1 Certain subgroups, including patients with therapy-related AML (t-AML), older patients (ie, those aged $60 years), patients with relapsed/refractory disease (RR-AML), and patients with AML progressing from an antecedent hematologic disorder, have a particularly poor outcome.2-8 In patients with high-risk AML, high-dose cytarabine and mitoxantrone (HiDAC/mito) is an effective and well-tolerated alternative to standard-dose cytarabine with an anthracycline.9-11 Submitted 5 August 2019; accepted 24 December 2019; published online 13 corresponding author (Olatoyosi Odenike; e-mail: todenike@ February 2020. DOI 10.1182/bloodadvances.2019000795. medicine.bsd.uchicago.edu). *K.E.C. and Y.H.K. contributed equally to this study. The full-text version of this article contains a data supplement. Deidentified individual participant data that underlie the reported results will be made © 2020 by The American Society of Hematology available by request up to 2 years after publication. Requests should be sent to the 25 FEBRUARY 2020 x VOLUME 4, NUMBER 4 599 Dysregulated epigenetic mechanisms, including aberrant DNA Table 1. Patient characteristics (n 5 46 patients) methylation, have been implicated in the pathogenesis of Characteristic Value AML.12-14 When used as single agents, the DNA methyltransferase Age, median (range), y 66 (21-83) inhibitors azacitidine (AZA) and decitabine have a complete remission (CR) rate between 7% and 25% in treatment-naive patients with Sex, n (%) AML.15-17 It is hypothesized that the clinical activity of these agents Male 27 (59) is mediated at least in part by epigenetic modulation of key genes Female 19 (41) 18-20 critical to myeloid leukemogenesis. In the current phase 1 study Subgroup, n (%) Downloaded from https://ashpublications.org/bloodadvances/article-pdf/4/4/599/1715665/advancesadv2019000795.pdf by UNIVERSITY OF CHICAGO LIBRARY user on 04 March 2020 of patients with high-risk AML, including relapsed or refractory Untreated de novo AML 5 (11) disease, AZA was given before HiDAC/mito based on the hypothesis that epigenetic priming with a hypomethylating Untreated t-AML 10 (22) agent prior to cytotoxic chemotherapy would sensitize malig- Untreated CMML-AML or MDS-AML* 5 (11) nant cells to chemotherapy and enhance the response to Relapsed/refractory 26 (56) treatment. The primary objective of the current study was to ECOG performance status, n (%) establish the recommended phase 2 dose of AZA when given 0 29 (63) in combination with HiDAC/mito. Secondary outcomes were to 1 15 (33) determine the safety of the combination regimen, response rates, and survival. 2 2 (4) Risk stratification (ELN criteria), n (%) Materials and methods Favorable 8 (17) Subjects Intermediate-1 9 (20) The study population included patients aged $18 years with Intermediate-2 6 (13) high-risk AML and an Eastern Cooperative Oncology Group Adverse 23 (50) performance status 0 to 2. AML was defined by using the 2008 Treatment history, n (%) 21 criteria of the World Health Organization. Patients with high- First relapse 17 (37) risk disease were defined as having t-AML, RR-AML, or de novo Beyond first relapse 5 (11) AMLinthoseaged$60 years, AML arising from myelodys- plastic syndrome (MDS-AML), myeloproliferative neoplasms in Primary refractory 4 (9) blast phase, and AML arising from chronic myelomonocytic Previous hypomethylating agent 14 (30) leukemia (CMML-AML). Molecular analysis for NPM1, FLT3,and All untreated 20 (44) CEBPA mutations and cytogenetic analysis were performed on All untreated aged $60 y 17 (37) pretreatment bone marrow biopsy specimens using Clinical – ECOG, Eastern Cooperative Oncology Group. Laboratory Improvement Amendments approved assays. Ge- *All patients with previous MDS or CMML received a hypomethylating agent before AML netic risk groups were defined according to the 2010 European diagnosis. Leukemia Network (ELN) risk stratification scheme.22 Patients were excluded if they had a diagnosis of acute promyelocytic leukemia, major surgery, concurrent anticancer therapy with Toxicity assessment the exception of hydroxyurea, or participation in other in- vestigational trials within 2 weeks before study entry. There Dose-limiting toxicity (DLT) was defined as any grade 4 or was no limit to the number of previous therapies. Prior AZA greater nonhematologic toxicity (except nausea/vomiting lasting # # or HiDAC exposure was permitted but not in the same 48 hours or liver function abnormalities lasting 48 hours), $ schedule as proposed in the current study. This single-center grade 3 nonhematologic toxicity lasting 7 days, or persistent trial was approved by the institutional review board at the bone marrow aplasia in the absence of bone marrow involvement $ University of Chicago and registered at www.clinicaltrials.gov as with disease for 56 days. Cohorts of 3 patients were treated at #NCT01839240. All participants provided written informed each dose level, and once the dose had been declared tolerable , consent. (0 of 3 DLTs or 2 of 6), additional patients could be enrolled to gain further experience at that dose level while further dose escalation was Study design and treatment plan ongoing. Thus, each dose level had 12 to 18 subjects. All toxicities and adverse events were recorded and graded according to the Cohorts of 3 patients were treated in a 3 1 3 dose escalation National Cancer Institute’s Common Toxicity Criteria for Adverse scheme. Patients received AZA at 37.5 mg/m2, 50 mg/m2,or Events, version 4.23 75 mg/m2 subcutaneously or IV once daily on days 1 to 5, followed by cytarabine 3000 mg/m2 given IV over 4 hours followed by Efficacy assessment mitoxantrone 30 mg/m2 given IV over 1 hour once each on days 6 and 10. The maximum dose of AZA to be explored was capped at Bone marrow aspirates and biopsies were performed to evaluate 75 mg/m2. Cytarabine and mitoxantrone dose reductions were the efficacy of this regimen: a nadir marrow biopsy was performed made for patients aged $70 years by 33% to 2000 mg/m2 of on day 17, and a biopsy to assess remission status was conducted cytarabine and 20 mg/m2 of mitoxantrone. Prophylactic antibiotics within 2 weeks of hematologic recovery (defined as absolute and tumor lysis prophylaxis were given according to institutional neutrophil count $1 3 109/L and platelet count $100 3 109/L) but guidelines. no later than day 42. Response criteria for CR, CR with incomplete 600 CAHILL et al 25 FEBRUARY 2020 x VOLUME 4, NUMBER 4 Table
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