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Sorafenib and Omacetaxine Mepesuccinate As a Safe and Effective Treatment for Acute Myeloid Leukemia Carrying Internal Tandem Du

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Sorafenib and Omacetaxine Mepesuccinate As a Safe and Effective Treatment for Acute Myeloid Leukemia Carrying Internal Tandem Du Original Article Sorafenib and Omacetaxine Mepesuccinate as a Safe and Effective Treatment for Acute Myeloid Leukemia Carrying Internal Tandem Duplication of Fms-Like Tyrosine Kinase 3 Chunxiao Zhang, MSc1; Stephen S. Y. Lam, MBBS, PhD1; Garret M. K. Leung, MBBS1; Sze-Pui Tsui, MSc2; Ning Yang, PhD1; Nelson K. L. Ng, PhD1; Ho-Wan Ip, MBBS2; Chun-Hang Au, PhD3; Tsun-Leung Chan, PhD3; Edmond S. K. Ma, MBBS3; Sze-Fai Yip, MBBS4; Harold K. K. Lee, MBChB5; June S. M. Lau, MBChB6; Tsan-Hei Luk, MBChB6; Wa Li, MBChB7; Yok-Lam Kwong, MD 1; and Anskar Y. H. Leung, MD, PhD 1 BACKGROUND: Omacetaxine mepesuccinate (OME) has antileukemic effects against acute myeloid leukemia (AML) carrying an internal tandem duplication of Fms-like tyrosine kinase 3 (FLT3-ITD). A phase 2 clinical trial was conducted to evaluate a combina- tion treatment of sorafenib and omacetaxine mepesuccinate (SOME). METHODS: Relapsed or refractory (R/R) or newly diagnosed patients were treated with sorafenib (200-400 mg twice daily) and OME (2 mg daily) for 7 (first course) or 5 days (second course on- ward) every 21 days until disease progression or allogeneic hematopoietic stem cell transplantation (HSCT). The primary endpoint was composite complete remission, which was defined as complete remission (CR) plus complete remission with incomplete hematologic recovery (CRi). Secondary endpoints were leukemia-free survival (LFS) and overall survival (OS). RESULTS: Thirty-nine R/R patients and 5 newly diagnosed patients were recruited. Among the R/R patients, 28 achieved CR or CRi. Two patients showed partial remission, and 9 patients did not respond. Among the 5 newly diagnosed patients, 4 achieved CR, and 1 achieved CRi. The median LFS and OS were 5.6 and 10.9 months, respectively. Prior Fms-like tyrosine kinase 3 (FLT3) inhibitor exposure (P = .007), 2 or more inductions (P = .001), and coexisting IDH2 (P = .008) and RUNX1 mutations (P = .003) were associated with lower CR/CRi rates. HSCT consolidation and deep molecular responses (defined as an FLT3-ITD variant allelic frequency [VAF] ≤ 0.1% or a nucleophosmin 1 [NPM1] mutant VAF ≤ 0.01%) were associated with better OS and LFS. Prior FLT3 inhibitor exposure and 2 or more inductions were associated with inferior LFS. CONCLUSIONS: SOME was safe and effective for R/R and newly diagnosed FLT3-ITD AML. Cancer 2019;0:1-10. © 2019 American Cancer Society. KEYWORDS: acute myeloid leukemia (AML), internal tandem duplication of Fms-like tyrosine kinase 3 (FLT3-ITD), minimal residual disease, omacetaxine mepesuccinate, sorafenib. INTRODUCTION Acute myeloid leukemia (AML) is a heterogeneous group of diseases characterized by distinct clinicopathologic, cytogenetic, and genetic features.1-3 Induction chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT) are the mainstays of treatment. Clinicopathologic and genetic features at diagnosis may predict treatment responses and long- term outcomes.4 Internal tandem duplication of Fms-like tyrosine kinase 3 (FLT3-ITD) is one of the most common mutations in AML2 and occurs in 25% to 35% of adult patients, particularly those with normal cytogenetics or rarely a t(6;9) translocation. Relapses after conventional chemotherapy are frequent in FLT3-ITD+ AML and portend an 5 extremely poor outcome. Salvage chemotherapy results in remission in <20% of cases, with a median duration of sur- vival of merely 3 months.6,7 A combination of a tyrosine kinase inhibitor targeting Fms-like tyrosine kinase 3 (FLT3) with standard induction and consolidation chemotherapy has emerged as a new standard of care for newly diagnosed FLT3-ITD AML.8 In 9,10 relapsed or refractory (R/R) FLT3-ITD+ AML, the effects of FLT3 inhibitors have been modest and transient. In vitro drug sensitivity testing with primary leukemia samples has identified omacetaxine mepesuccinate (OME; also known as homoharringtonine or HHT) as an effective adjunct for the treatment of FLT3-ITD AML.11 OME acts by inhibiting Corresponding author: Anskar Y. H. Leung, MD, PhD, Department of Medicine, Queen Mary Hospital, Pokfulam Road, Room K418, K Block, Hong Kong, China; ayhleung@ hku.hk 1 Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; 2 Division of Haematology, Department of Pathology, Queen Mary Hospital, Hong Kong, China; 3 Department of Pathology, Hong Kong Sanatorium and Hospital, Hong Kong, China; 4 Department of Medicine, Tuen Mun Hospital, Hong Kong, China; 5 Department of Medicine, Princess Margaret Hospital, Hong Kong, China; 6 Department of Medicine, Queen Elizabeth Hospital, Hong Kong, China; 7 Department of Clinical Oncology, Prince of Wales Hospital, Hong Kong, China We thank all the patients and their families for participating in the trial and contributing clinical samples. Additional supporting information may be found in the online version of this article. DOI: 10.1002/cncr.32534, Received: May 16, 2019; Revised: August 16, 2019; Accepted: August 28, 2019, Published online Month 00, 2019 in Wiley Online Library (wileyonlinelibrary.com) Cancer Month 0, 2019 1 Original Article global messenger RNA translation. FLT3-ITD+ AML reaction would require cessation of sorafenib until clini- appears to be particularly sensitive to the antileuke- cal improvement, and sorafenib would be reinstated at mia effect of OME. We showed previously that signif- 200 mg twice daily. icant synergism occurred between FLT3 inhibitors and OME in leukemic samples in vitro and in vivo as murine Definition of Responses xenografts.11 Importantly, preliminary clinical data have A bone marrow (BM) examination was performed on day indicated that such synergism occurs in patients with R/R 21 after the commencement of treatment. Patients who did 11 FLT3-ITD+ AML. In this report, we describe the entire not achieve CR/CRi received a second course of SOME cohort of patients with FLT3-ITD+ AML treated with (7 days of OME), and the BM examination was repeated sorafenib and omacetaxine mepesuccinate (SOME). on day 21 of the second cycle. The best BM response was documented, and those who did not achieve CR/CRi after the second cycle exited the trial. CR was defined as 5% MATERIALS AND METHODS < blasts in BM or blood with an absolute neutrophil count Patients 9 9 ≥1 × 10 /L and a platelet count ≥100 × 10 /L. CRi was Adult patients (age ≥ 18 years) with FLT3-ITD+ AML defined as <5% blasts in BM or blood but with incom- who relapsed or were refractory to induction chemother- plete hematologic recovery. Partial responses (PR) and no apy as well as newly diagnosed patients with FLT3-ITD+ responses (NR) were defined as ≥50% and <50% reduc- AML who were unfit for or declined chemotherapy were tions of circulating or BM blasts, respectively, and in both recruited. All patients gave informed consent for treat- cases, the absolute blast counts were >5% of nucleated cells. ment. The study was approved by the institutional review board in accordance with the Declaration of Helsinki and Transfusion Dependence was registered at ClinicalTrials.gov. Assuming a 20% to The numbers of packed cell units and platelet transfusions 30% increase in the response rate in comparison with (1 adult therapeutic dose for each platelet transfusion) for sorafenib monotherapy,12 a type I error of 0.05, and a sta- patients who achieved CR/CRi were summed on a monthly tistical power of 0.8, we needed approximately 40 patients basis from the time they achieved CR/CRi to the time of for this study (https ://clinc alc.com/stats/ sampl esize.aspx). death, disease progression, or allogeneic HSCT. SOME Regimen Mutation Profile Sorafenib was administered continuously from day 1 Mutation profiling was performed at diagnosis or before (400 mg twice daily orally). OME was administered from SOME treatment. Genomic DNA was extracted with day 1 to day 7 (2 mg/d intravenously) in the first 21-day the QIAamp DNA Blood Mini Kit (Qiagen, Hilden, cycle. After the first cycle, patients achieving complete Germany) and was analyzed with MiSeq next-generation remission (CR) or complete remission with incomplete sequencing (Illumina, San Diego, California) based on hematologic recovery (CRi) received OME from day 1 to the TruSight myeloid sequencing panel (Illumina). The day 5 for subsequent 21-day cycles. For patients achieving panel targeted 54 genes and covered the full coding se- a partial response, OME continued to be administered quence of 15 genes and exonic hotspots for the other from day 1 to day 7 per 21-day cycle until CR/CRi, after 39 genes. The workflows of MiSeq sequencing library which OME was given from day 1 to day 5 for subse- preparation, variant calling, and annotation as well as the quent cycles. Patients with nonremission were withdrawn detection of FLT3-ITD by ITD seek have been described from the study. SOME was continued until allogeneic elsewhere.11,13 Complex insertions and deletions were HSCT, a loss of response, or withdrawal from the study detected by an in-house designed algorithm (INDEL due to adverse events. seek) on a Cray XC30 supercomputer. Adverse Events Measurement of the FLT3-ITD Variant Allelic Investigator-assessed adverse events were graded Frequency and Detection of Tyrosine Kinase according to the National Cancer Institute’s Common Domain Mutations Terminology Criteria for Adverse Events (version 4.03). FLT3-ITD was evaluated by polymerase chain reaction In the event of treatment-related pancytopenia, gran- (PCR) with primers covering exons 14 to 15 followed by ulocyte colony-stimulating factor and prophylactic capillary electrophoresis. The size of FLT3-ITD clones, antifungal therapy were given. Patients who developed a represented as the variant allelic frequency (VAF), was grade 2 or higher maculopapular rash or hand-foot skin evaluated by their area under the curve with reference 2 Cancer Month 0, 2019 Sorafenib and Omacetaxine in FLT3 -ITD AML/Zhang et al to that of the sum of FLT3-ITD and FLT3 wild-type Study Endpoints and Statistical Analysis clones.
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