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Pracinostat Plus Azacitidine in Older Patients With Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia: results of a phase 2 study Guillermo Garcia-Manero, University of Texas MD Anderson Cancer Center Yasmin Abaza, University of Texas MD Anderson Cancer Center Koichi Takahashi, University of Texas MD Anderson Cancer Center Bruno C. Medeiros, Stanford University Martha Arellano, Emory University Samer K. Khaled, City of Hope Mrinal Patnaik, Mayo Clinic Olatoyosi Odenike, University of Chicago Hamid Sayar, Indiana University Mohan Tummala, Mercy Hospital Only first 10 authors above; see publication for full author list. Journal Title: Blood Advances Volume: Volume 3, Number 4 Publisher: American Society of Hematology: Blood Advances | 2019-02-26, Pages 508-518 Type of Work: Article | Final Publisher PDF Publisher DOI: 10.1182/bloodadvances.2018027409 Permanent URL: https://pid.emory.edu/ark:/25593/tnqtm Final published version: http://dx.doi.org/10.1182/bloodadvances.2018027409 Copyright information: © 2019 by The American Society of Hematology. Accessed September 27, 2021 11:24 PM EDT REGULAR ARTICLE Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia: results of a phase 2 study Guillermo Garcia-Manero,1 Yasmin Abaza,1 Koichi Takahashi,1 Bruno C. Medeiros,2 Martha Arellano,3 Samer K. Khaled,4 Mrinal Patnaik,5 Olatoyosi Odenike,6 Hamid Sayar,7 Mohan Tummala,8 Prapti Patel,9 Lori Maness-Harris,10 Robert Stuart,11 Elie Traer,12 Kasra Karamlou,13 Abdulraheem Yacoub,14 Richard Ghalie,15 Ruben Giorgino,16 and Ehab Atallah17 1Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX; 2Department of Hematology, Stanford University, Stanford, CA; 3Department of Hematology, Emory University School of Medicine, Atlanta, GA; 4Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA; 5Department of Hematology, Mayo Clinic, Rochester, MN; 6Division of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL; 7Department of Hematology and Oncology, Indiana University, Indianapolis, IN; 8Mercy Hospital, Springfield, MO; 9Department of Hematology, University of Texas Southwestern Medical Center, Dallas, TX; 10Department of Hematology and Oncology, University of Nebraska Medical Center, Omaha, NE; 11Section of Hematological Malignancies and Blood/Marrow Transplantation, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC; 12Department of Hematologic Malignancies, Oregon Health and Science University, Portland, OR; 13Arizona Oncology, Tempe, AZ; 14Department of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Cancer Center, Westwood, KS; 15MEI Pharma, Inc., San Diego, CA; 16Helsinn Healthcare, SA, Lugano, Switzerland; and 17Department of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity Key Points in acute myeloid leukemia (AML), has shown synergistic antitumor activity when combined • Pracinostat in combi- with azacitidine. This single-group, multicenter phase 2 study assessed the safety and efficacy nation with azacitidine of pracinostat combined with azacitidine in patients who were at least 65 years old with newly is well tolerated and diagnosed AML and who were ineligible for standard induction chemotherapy. Patients active in the frontline received pracinostat 60 mg/d, 3 d/wk, for 3 consecutive weeks, plus azacitidine 75 mg/m2 daily treatment of older for 7 days in a 28-day cycle. Primary endpoints were complete remission (CR), CR with patients with AML. incomplete count recovery (CRi), and morphologic leukemia-free state (MLFS) rates of the • The CR rate of 42% combination. Secondary endpoints included safety, progression-free survival (PFS), and and 1-year OS rate of overall survival (OS) of the regimen. Fifty patients (33 de novo, 12 secondary, and 5 therapy- 62% in patients unfit related AML) were enrolled. Twenty-six patients (52%) achieved the primary endpoint of for intensive therapy CR (42%), CRi (4%), and MLFS (6%). Median OS and PFS were 19.1 months (95% confidence compared favorably with historic azacitidine interval [CI], 10-26.5 months) and 12.6 months (95% CI, 10-17.7 months), respectively, with a data. 1-year OS rate of 62%. Forty-three patients (86%) experienced at least 1 grade 3 or worse treatment-emergent adverse event with the combination, with infections (52%), thrombo- cytopenia (46%), and febrile neutropenia (44%) reported as the most common toxicities. The 30- and 60-day all-cause mortality rates were 2% and 10%, respectively. DNA sequencing revealed somatic mutations at baseline, and clearance rates correlated with response to treatment. Pracinostat plus azacitidine is a well-tolerated and active regimen in the frontline treatment of older patients with AML unfit for intensive therapy. A larger controlled trial is ongoing. This trial was registered at www.clinicaltrials.gov as #NCT01912274. Introduction Acute myeloid leukemia (AML) is a heterogeneous disease characterized by clonal proliferation of poorly differentiated cells of the hematopoietic system. It is typically a disease of older patients, with an average diagnosis age of 67 years.1 Although the cure rate for AML patients 60 years or younger using intensive Submitted 16 October 2018; accepted 5 January 2019. DOI 10.1182/ The full-text version of this article contains a data supplement. bloodadvances.2018027409. © 2019 by The American Society of Hematology A synopsis of the study protocol is available in the supplemental data. Individual participant data will not be shared. 508 26 FEBRUARY 2019 x VOLUME 3, NUMBER 4 chemotherapy (IC) approaches 35% to 40%, it remains poor in ineligible to receive standard induction chemotherapy (eg, because older patients, typically not exceeding 15%.2-6 of age, performance score, or comorbidities); had to have an Eastern Hypomethylating agents have shown modest activity in older Cooperative Oncology Group (ECOG) performance status of 0 to 2; white blood cell count less than 30 000/mL; total bilirubin patients with newly diagnosed AML and are acceptable treatment 3 options for patients deemed unfit for IC.1 Two phase 3 randomized and serum creatinine 2 or less upper limit of normal; aspartate aminotransferase and alanine aminotransferase 2.5 or less 3 upper studies comparing azacitidine with conventional care regimens in ’ older patients with AML demonstrated an improvement in median limit of normal; and Fridericia s correction of QT interval of 450 ms overall survival (OS) for azacitidine.7,8 Similarly, decitabine was or less (males) or 470 ms (females). Prior therapy with lenalidomide, also found to improve response rates and OS in this patient immunosuppressive agents, low-dose chemotherapy, or 1 cycle subset when compared with other low-intensity therapies.9 of hypomethylating agent therapy for an antecedent hematologic Despite these results, the majority of older patients with AML disorder or AML was allowed. Major exclusion criteria were treated with these agents will relapse and succumb to their disease. favorable cytogenetic abnormalities [eg, t(15;17), t(8;21), Population-based studies of patients 60 years of age or older have t(16;16), del(16q), or inv(16)]; candidate for IC within the next 10,11 4 months; uncontrolled comorbidities; active central nervous system shown 3-year survival rates between 6% and 24%, and cure in 6 disease; prior therapy with HDAC inhibitors, stem cell trans- only 5% to 15%. plantation, IC, or hematopoietic growth factors within 7 days of Histone deacetylases (HDACs) and DNA methyltransferases study enrollment; uncontrolled active systemic infections; and (DNMTs) are critical chromatin-modifying enzymes that regulate malabsorption. gene expression through governing the methylation of CpG islands in the promoter region of genes.12,13 Overexpression of both Study design and treatment enzyme classes promotes leukemogenesis through aberrant This was a phase 2, multicenter, open-label, single-arm, 2-stage study epigenetic silencing of important regulatory and tumor suppressor 14 designed to determine the safety and efficacy of the combination genes. Combining DNMT and HDAC inhibitors have been found regimen in the treatment of older patients with AML. Azacitidine in vitro to synergistically induce gene reexpression, leading to 2 15-17 75 mg/m was administered intravenously or subcutaneously for the tumor cell apoptosis and differentiation. This synergy has been first 7 days or in a 5-2-2 schedule in combination with pracinostat observed clinically in a number of promising early-phase clinical trials 60 mg orally daily, every other day, 3 days a week, for 3 consecutive for both AML and high-risk myelodysplastic syndromes (MDS), but 18-25 weeks in a 28-day cycle. Treatment was continued until disease were not confirmed in subsequent controlled phase 2 studies. progression (PD), intolerable toxicity, intercurrent illnesses, or per Pracinostat, a potent oral pan-HDAC inhibitor, has shown superior patient request. Because median time to response for azacitidine was pharmacokinetic and pharmacodynamic properties compared with previously reported to be 3 to 3.5 months, attempts were made to other HDAC inhibitors.26-29 Preclinical and clinical studies have avoid premature drug discontinuation.31-33 Patients were allowed to demonstrated the antitumor activity of pracinostat in hematological undergo stem cell transplantation if they
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