Acute Myeloid Leukemia: Individualizing Therapy in Progressive Disease

Transcription

1 TREATMENT UPDATE Acute Myeloid Leukemia: Individualizing Therapy in Progressive Disease FACULTY Elias Jabbour, MD Associate Professor Department of Leukemia University of Texas M. D. Anderson Cancer Center Houston, Texas STAFF Terrence Fagan Associate Managing Editor Clinical Care Options, LLC Gordon Kelley Senior Clinical Editor Clinical Care Options, LLC Andrew D. Bowser, ELS, CCMEP Editorial Director, Hematology/Oncology Clinical Care Options, LLC Jim Mortimer Senior Director, Oncology Programs and Partnership Development Clinical Care Options, LLC Jointly sponsored by the Annenberg Center for Health Sciences at Eisenhower and Clinical Care Options, LLC This activity is supported by educational grants from Boehringer Ingelheim Pharmaceuticals, Inc. Copyright 2014 Clinical Care Options, LLC. All rights reserved. 1

2 DISCLOSURES The Annenberg Center assesses conflict of interest with its instructors, planners, managers, and other individuals who are in a position to control the content of CME activities. All relevant conflicts of interest that are identified are thoroughly vetted by the Annenberg Center for fair balance, scientific objectivity of studies utilized in this activity, and patient care recommendations. The Annenberg Center is committed to providing its learners with high-quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest. The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Elias Jabbour, MD, has no significant financial relationships to disclose. Terrence Fagan has no significant financial relationships to disclose. Gordon Kelley has no significant financial relationships to disclose. Andrew D. Bowser, ELS, CCMEP, has no significant financial relationships to disclose. Jim Mortimer has no significant financial relationships to disclose. The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: The following planners and managers, Laura Excell, ND, NP, MS, MA, LPC, NCC; Trace Hutchison, PharmD; Samantha Mattiucci, PharmD, CCMEP; and Jan Schultz, RN, MSN, CCMEP hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. Charles E. Willis, Director of Continuing Education (Annenberg Center), consults for Pfizer, Inc. DISCLOSURE OF UNLABELED USE This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The Annenberg Center, Postgraduate Institute for Medicine (PIM), Clinical Care Options, and activity supporters do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the Annenberg Center, PIM, Clinical Care Options, and activity supporters. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. DISCLAIMER Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient s conditions and possible contraindications on dangers in use, review of any applicable manufacturer s product information, and comparison with recommendations of other authorities. Copyright 2014 Clinical Care Options, LLC. All rights reserved. 2

3 GOAL The goal of this activity is to provide participants with current, evidence-based expert guidance on selecting optimal treatment for patients with acute myeloid leukemia. TARGET AUDIENCE This program is intended for physicians and other healthcare professionals who provide care for patients with acute myeloid leukemia. LEARNING OBJECTIVES Upon completion of this activity, participants should be able to: Utilize diagnostic and risk-stratification strategies to facilitate timely initiation of treatment and optimal ongoing management for patients with acute myeloid leukemia Determine patient eligibility for intensive and nonintensive therapy for acute myeloid leukemia Select optimal treatments for patients in all stages of the disease, based on an understanding of the biological pathways involved in acute myeloid leukemia PHYSICIAN CONTINUING MEDICAL EDUCATION Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Annenberg Center for Health Sciences at Eisenhower and Clinical Care Options, LLC. The Annenberg Center for Health Sciences at Eisenhower is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation The Annenberg Center for Health Sciences at Eisenhower designates this enduring material for a maximum of 0.75 AMA PRA Category 1 Credit. Physicians should claim only the credit commensurate with the extent of their participation in the activity. INSTRUCTIONS FOR CREDIT Participation in this self-study activity should be completed in approximately 0.75 hour. To successfully complete this activity and receive credit, participants must follow these steps during the period from May 30, 2014 through May 29, 2015: 1. Register online at 2. Read the target audience, learning objectives, and faculty disclosures. 3. Study the educational activity online or printed out. 4. Submit answers to the posttest questions and evaluation questions online. You must receive a test score of at least 65% and respond to all evaluation questions to receive a certificate. After submitting the evaluation, you may access your online certificate by selecting the certificate link on the posttest confirmation page. Records of all CME activities completed can be found on the "CME Manager" page. There are no costs/fees for this activity. DISCLAIMER The materials published on the Clinical Care Options Web site reflect the views of the reviewers or authors of the CCO material, not those of Clinical Care Options, LLC, the CME provider, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials. Copyright 2014 Clinical Care Options, LLC. All rights reserved. 3

4 Acute Myeloid Leukemia: Individualizing Therapy in Progressive Disease CONTENTS Introduction... 5 Case Report: Newly Diagnosed Acute Myeloid Leukemia... 5 Case Report: Elderly AML Patient With Comorbidities... 6 Case Report: Relapsed AML... 8 Postactivity Assessment... 9 Posttest References Copyright 2014 Clinical Care Options, LLC. All rights reserved. 4

5 Introduction In the setting of acute myeloid leukemia (AML), the primary goal is achieving and maintaining a complete response (CR), which can significantly improve survival. Patients who achieve a CR have a probability of recurrence of < 10% after 3 years. In addition, a key goal in AML treatment is to help patients emerge from induction therapy with the ability to tolerate subsequent, more intensive consolidation treatment in order to achieve durable disease control. However, the traditional standard of care, the 3+7 regimen of an anthracycline plus cytarabine, is suboptimal, and many patients will relapse in the absence of a CR. In addition, older patients are at increased risk of having unfavorable cytogenetics and often have poor performance status and comorbidities. Overall, despite considerable progress in the treatment of AML, two thirds of younger patients and 90% of older patients with AML are likely to die of their disease. [1] The identification of genetic mutations with prognostic significance and the emergence of new agents such as hypomethylating agents and FLT inhibitors are changing the therapeutic landscape for AML. To help clinicians better understand the evolving AML treatment paradigm, in this interactive educational activity, Elias Jabbour, MD, of the University of Texas M. D. Anderson Cancer Center, will ask specific questions regarding the clinical management of patients. After you submit your answers, you will be able to see how your peers responded, as well as review Dr. Jabbour s discussion of those questions and recommendations for practice. Case Report: Newly Diagnosed Acute Myeloid Leukemia A 45-year-old man presents with fatigue, low-grade fever, and petechia. Blood analysis Complete blood count showed pancytopenia White blood cell count: 25,000/mm 3 Platelets: 110,000/mm 3 Hemoglobin: 9.6 g/dl Differential count Blasts: 32% Polymorphonuclear neutrophils: 15% Bone marrow: 87% blasts (myeloperoxidase positive) Cytogenetics: diploid karyotype Molecular biology Absence of FLT3-ITD mutation Positive for NPM1 mutation Diagnosis: AML Which of the following options would be your choice for initial treatment in this patient? A. 3+7 regimen B. High-dose cytarabine plus idarubicin C. Azacitidine D. High-dose cytarabine plus vorinostat E. 3+7 plus cladribine F. Unsure San Miguel In the setting of AML, determining the karyotype and conducting molecular testing are key to determining what kind of therapy to offer. To date, the most important mutations to test for are the FLT3-ITD mutation and NPM1 mutation. If a patient tests positive for the FLT3- ITD mutation, they have a worse prognosis than if they have wild-type FLT3. [2-4] Among patients with wild-type FLT3-ITD, those who are positive for a NPM1 mutation have a better prognosis. [5] Copyright 2014 Clinical Care Options, LLC. All rights reserved. 5

6 This patient had a diploid karyotype, wild-type FLT3-ITD, and NPM1 mutation. Therefore, overall, he was classified as having good-risk AML. For decades, the standard of care for induction chemotherapy for AML has been the 3+7 regimen, combining an anthracycline (typically daunorubicin) with cytarabine. [1] This regimen is obsolete for several reasons. One is the dose of daunorubicin. Increasing the daily dose of daunorubicin from 45 mg/m 2 to 90 mg/m 2 in younger adults (15-60 years of age) with AML has been shown to produce significantly higher CR rates (57% vs 71%, respectively; P <.001) and longer overall survival (OS) (16 vs 24 months; P =.003). [6] The problem with giving the higher 90 mg/m 2 dose of daunorubicin is that within 2 cycles of induction, the patient will have received a cumulative dose of approximately 500 mg/m 2, which is a limiting dose due to increased risk of myocardial toxicity. Studies have shown that idarubicin is better than daunorubicin as induction therapy for patients with newly diagnosed AML. In a recent meta-analysis (10 trials; N = 4060), idarubicin was associated with a significant benefit for CR (relative risk: 1.23), event-free survival (HR: 0.64), and OS (HR: 0.88), but not disease-free survival (HR: 0.90). [7] A previous study, also in patients with newly diagnosed AML (N = 2157), showed that both idarubicin and mitoxantrone were superior to daunorubicin in terms of both CR and disease-free survival (37% vs 37% vs 29%, respectively), although the 5-year OS rates were similar (~ 31% to 34%). [8] With these results, idarubicin rather than daunorubicin induction is a better option for this patient. Keep in mind that this is a young patient who may be a candidate for high-dose rather than standard-dose cytarabine. Recent studies include the EORTC-GIMEMA AML-12 phase III trial that showed higher 6-year survival and higher CR rates in young patients (younger than 46 years of age) with high-dose cytarabine vs the standard dose added to induction therapy. [9] At 6 years, OS in this group was 43.3% for standard-dose cytarabine vs 51.9% for high dose cytarabine (P =.003). Therefore, this patient should receive induction chemotherapy and consolidation using idarubicin and high-dose cytarabine. Case Report: Elderly AML Patient With Comorbidities A 76-year-old patient presents with serious fatigue. He has a history of diabetes and hypertension, with a myocardial infarction 2 years earlier. His mild congestive heart failure is controlled with medication. He has an Eastern Cooperative Oncology Group (ECOG) performance status of 2. Blood analysis White blood cell count: 70,000/mm 3 Platelets: 20,000/mm 3 Hemoglobin: 8 g/dl Blasts: 80% (peroxidase positive) Bone marrow: 70% blasts (peroxidase positive) Cytogenetics: karyotype not available Diagnosis: AML Which of the following options would be your choice for treatment? A. Decitabine B. Hydroxyurea C. 3+7 regimen D. Azacitidine E. Low-dose cytarabine F. Supportive care G. Unsure Copyright 2014 Clinical Care Options, LLC. All rights reserved. 6

7 Despite recent progress in the treatment of younger patients with AML, little progress has been made in improved therapies for patients 70 years of age and older. These patients have a very poor prognosis: median survival for this group treated with intensive chemotherapy in a retrospective study was 4.2 months in the period of , with only 6% still alive at 5 years. [10] Between 2000 and 2009, this improved only slightly, with median survival of 5.1 months. Reasons include poor tolerance and a high mortality rate with intensive chemotherapy. Elderly patients also have more comorbidities and a poor performance status. They also may have more resistant disease, which can be associated with adverse cytogenetics, and more adverse features, such as molecular abnormalities. Therefore, these patients are typically not a good fit for chemotherapy. Prognostic models have been developed for elderly patients with AML based on standard, readily available baseline characteristics. A mltivariate analysis by Kantarjian and colleagues [11] of prognostic factors in this group found that older than 75 years of age, unfavorable karyotype, ECOG performance status 2, treatment outside a laminar air flow room, duration of antecedent hematologic disorder > 12 months, lactate dehydrogenase > 600 µ/l, and creatinine > 1.3 mg/dl had independent adverse significance for survival. In my practice, I use this scoring system before I decide on intensive chemotherapy. This case patient is not fit for intensive chemotherapy but could receive nonintensive chemotherapy. Options include low-dose cytarabine, but, as you will see below, this may not be the best regimen. Another possible option is azacitidine, a hypomethylating agent, approved for the treatment of myelodysplastic syndromes. The approval was expanded in 2009 to include highrisk patients with 20% to 30% bone marrow blasts considered AML with features of myelodysplastic syndromes based on results from the AZA-001 study that showed significant improvement in survival rates [12] : a 2-year survival rate of 50% vs 16% without azacitidine (P =.004), with median survival times of 24.5 months vs 16.0 months, respectively (P =.004). Kantarjian and colleagues [13] conducted a randomized, open-label phase III study (N = 485) to compare another hypomethylating agent, decitabine, vs patient choice of either supportive care or low-dose cytarabine (20 mg/m 2 /day for 10 days every 4 weeks). At the time of the primary analysis (2009 cutoff), no OS benefit was observed in the decitabine group, but an unplanned exploratory subgroup analysis (2010 cutoff) showed a significant survival benefit. Response rates favored decitabine for all subgroups, specifically including patients 75 years of age or older (odds ratio: 5.94; P =.0006). Improved survival, however, was based on positive prognostic factors; factors negatively associated with OS included advanced age (75 years of older vs younger than 70 years of age; P =.001), poorer baseline ECOG performance status (P =.0321), poor cytogenetics (P =.001), higher bone marrow blast counts (P =.0045), low baseline platelet counts (P =.0015), and high white blood cell counts (P =.0151). [14] For this case patient, I would use nonintensive chemotherapy, with decitabine as my first choice and azacitidine as my second choice. I recommend clinical trials as well. Studies of clofarabine and other hypomethylating agents are building on this experience with decitabine and azacitidine in AML in clinical trials. Another agent in clinical trials that may be appropriate for this patient is the polo-like kinase 1 (PLK1) inhibitor volasertib. PLK1 is involved in cell mitosis, and it is overexpressed in AML, playing a critical role during proliferation. PLK1 inhibition has been shown to preferentially block leukemic cells vs normal cells, making it a promising therapeutic target for treating AML. [15] In a phase II randomized trial in patients with newly diagnosed AML ineligible for intensive treatment, volasertib plus low-dose cytarabine was compared with low-dose cytarabine alone. In preliminary results, the volasertib cohort demonstrated significant improvement in CR and a trend for event-free survival benefit. [16] A phase III study of volasertib in patients aged 65 years or older with previously untreated AML (POLO-AML-2) is currently under way. [17] Copyright 2014 Clinical Care Options, LLC. All rights reserved. 7

8 Case Report: Relapsed AML A 67-year-old black woman was diagnosed with AML (diploid karyotype). She was treated with the 3+7 regimen followed by high-dose cytarabine. She achieved an initial CR that lasted 4 months and then she relapsed. She was referred to us in reasonable health. She has no siblings. Blood analysis White blood cell count: 25,000/mm 3 Platelets: 110,000/mm 3 Hemoglobin: 8.2 g/dl Differential count Blasts: 32% Polymorphonuclear neutrophils: 15% Eosinophils: 12% Bone marrow: 87% blasts (myeloperoxidase positive) Cytogenetics: diploid karyotype Molecular biology: FLT3-ITD positive (allele burden: 80%) Which of the following options would you recommend for treatment in this patient? A. Hypomethylating agent B. High-dose cytarabine plus idarubicin C. Allogeneic stem cell transplantation D. Clinical trial E. Retreatment with the 3+7 regimen F. Palliative care G. Unsure This patient should be encouraged to enroll on a clinical trial. Patients who fail induction consolidation and relapse typically do poorly long term. The major predictive factor for outcome is duration of first CR: more than 1 year, 6 months to 1 year, or fewer than 6 months. Patients who relapse within 4 months should be enrolled on a clinical trial. The only reasonable approach in this case other than a clinical trial is allogeneic stem cell transplantation, which has a cure rate of 10% to 15%. However, the fact that she has no siblings limits her donor options for transplantation. This patient was positive for FLT3-ITD, so a combination regimen involving a FLT3 inhibitor plus chemotherapy may be effective. Other possible options include sorafenib, a pan-tyrosine kinase inhibitor with activity against FLT3 in AML. [18] A phase II study showed the combination of sorafenib plus azacitidine was effective in patients with relapsed AML and FLT3-ITD. [19] Other alternatives include quizartinib (AC-220), a potent, selective FLT3 inhibitor that has shown strong efficacy (a 47% cumulative CR rate) in a phase II study in relapsed/refractory AML. [20] A phase III study is under way comparing quizartinib monotherapy vs salvage therapy in patients with FLT3-ITD positive AML refractory to frontline treatment. [21] Another investigational agent being studied in FLT3-mutant AML is crenolanib, a selective type I pan-flt3 inhibitor. [22,23] This case patient might also benefit from a combination of FLT3 inhibitors and hypomethylating agents. For example, in a randomized phase II study in patients with either relapsed/refractory AML or elderly treatment-naive patients with high-risk AML, the novel hypomethylating agent SGI-110 given for 5 days at 60 mg/m 2 induced responses of approximately 25%. [24] The bottom line for this patient is that she should be enrolled on a clinical trial of a combination of chemotherapy plus an FLT3-ITD inhibitor and then transplantation if possible. Copyright 2014 Clinical Care Options, LLC. All rights reserved. 8

9 To summarize: First, in newly diagnosed AML, the 3+7 regimen is a poor standard of care; highdose cytarabine and idarubicin, with or without an additional agent, is preferable. Second, elderly patients with AML and comorbidities are typically not fit for chemotherapy; therefore, hypomethylating agents are preferred. Third, patients with relapsed FLT3-ITD positive AML should be enrolled on a clinical trial and receive a FLT3 inhibitor, with or without hypomethylating agents. Postactivity Assessment Thank you for participating in this activity. To assess how much you learned, please complete the following 3 postactivity assessment questions: POST-ACTIVITY QUESTION 1 A 45-year-old man presents with fatigue, low-grade fever, and petechia. Blood analysis Complete blood count showed pancytopenia White blood cell count: 25,000/mm 3 Platelets: 110,000/mm 3 Hemoglobin: 9.6 g/dl Differential count Blasts: 32% Polymorphonuclear neutrophils: 15% Bone marrow: 87% blasts (myeloperoxidase positive) Cytogenetics: diploid karyotype Molecular biology Absence of FLT3-ITD mutation Positive for NPM1 mutation Diagnosis: AML Which of the following options would be your choice for initial treatment in this patient? A. 3+7 regimen B. High-dose cytarabine plus idarubicin C. Azacitidine D. High-dose cytarabine plus vorinostat E. 3+7 plus cladribine F. Unsure POST-ACTIVITY QUESTION 2 A 76-year-old patient presents with serious fatigue. He has a history of diabetes and hypertension, with a myocardial infarction 2 years earlier. His mild congestive heart failure is controlled with medication. He has an Eastern Cooperative Oncology Group (ECOG) performance status of 2. Blood analysis White blood cell count: 70,000/mm 3 Platelets: 20,000/mm 3 Hemoglobin: 8 g/dl Blasts: 80% (peroxidase positive) Bone marrow: 70% blasts (peroxidase positive) Cytogenetics: karyotype not available Diagnosis: AML Copyright 2014 Clinical Care Options, LLC. All rights reserved. 9

10 Which of the following options would be your choice for treatment? A. Decitabine B. Hydroxyurea C. 3+7 regimen D. Azacitidine E. Low-dose cytarabine F. Supportive care G. Unsure POST-ACTIVITY QUESTION 3 A 67-year-old black woman was diagnosed with AML (diploid karyotype). She was treated with the 3+7 regimen followed by high-dose cytarabine. She achieved an initial CR that lasted 4 months and then she relapsed. She was referred to us in reasonable health. She has no siblings. Blood analysis White blood cell count: 25,000/mm 3 Platelets: 110,000/mm 3 Hemoglobin: 8.2 g/dl Differential count Blasts: 32% Polymorphonuclear neutrophils: 15% Eosinophils: 12% Bone marrow: 87% blasts (myeloperoxidase positive) Cytogenetics: diploid karyotype Molecular biology: FLT3-ITD positive (allele burden: 80%) Which of the following options would you recommend for treatment in this patient? A. Hypomethylating agent B. High-dose cytarabine plus idarubicin C. Allogeneic stem cell transplantation D. Clinical trial E. Retreatment with the 3+7 regimen F. Palliative care G. Unsure Copyright 2014 Clinical Care Options, LLC. All rights reserved. 10

11 To receive free CME credit for this article, Please complete the following posttest online at: clinicaloptions.com/oncology POSTTEST Click on the appropriate response below. 1. Which of the following confers a worse prognosis in patients with acute myeloid leukemia (AML)? A. FLT3-ITD mutation B. Wild-type FLT3 C. NPM1 mutation D. Wild-type NPM1 2. In a study by Kantarjian and colleagues, all of the following have been identified as factors with independent negative prognosis for survival in elderly patients with AML EXCEPT which one? A. Older than 75 years of age B. Lactate dehydrogenase levels > 600 µ/l C. Hemoglobin levels 8 g/dl D. Complex karyotype E. Treatment outside a laminar airflow room 3. Which of the following statements regarding induction therapy in younger patients with AML is FALSE? A. Increasing a daily dose of daunorubicin from 45 to 90 mg/m 2 is shown to produce higher complete response rates and longer survival than at 45 mg/m 2 B. Treatment with 4-6 cycles of 90 mg/m 2 /day of daunorubicin is a superior regimen to 4-6 cycles of 45 mg/m 2 /day of daunorubicin C. Treatment with idarubicin was associated with a significant benefit for complete response and overall survival D. Idarubicin and mitoxantrone were shown to be superior to daunorubicin in terms of both complete response and disease-free survival but not overall survival Copyright 2014 Clinical Care Options, LLC. All rights reserved. 11

12 REFERENCES 1. Rowe JM. Optimal induction and post-remission therapy for AML in first remission. Hematology Am Soc Hematol Educ Program. 2009; Gale RE, Green C, Allen C, et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood. 2008;111: Whitman SP, Archer KJ, Feng L, et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res. 2001;61: Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99: Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358: Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009;361: Wang J, Yang YG, Zhou M, et al. Meta-analysis of randomised clinical trials comparing idarubicin + cytarabine with daunorubicin + cytarabine as the induction chemotherapy in patients with newly diagnosed acute myeloid leukaemia. PLoS One. 2013;8:e Mandelli F, Vignetti M, Suciu S,et al. Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10. J Clin Oncol. 2009;27: Willemze R, Suciu S, Meloni G, et al. High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: results of the EORTC-GIMEMA AML-12 trial. J Clin Oncol. 2014;32: Kantarjian H, O Brien S. Questions regarding frontline therapy of acute myeloid leukemia. Cancer. 2010;116: Kantarjian H, O Brien S, Cortes J, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer. 2006;106: Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010;28: Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or lowdose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30: Mayer J, Arthur C, Delaunay J, et al. Multivariate and subgroup analyses of a randomized, multinational, phase 3 trial of decitabine vs treatment choice of supportive care or cytarabine in older patients with newly diagnosed acute myeloid leukemia and poor- or intermediate-risk cytogenetics. BMC Cancer. 2014;14: Renner AG, Dos Santos C, Recher C, et al. Polo-like kinase 1 is overexpressed in acute myeloid leukemia and its inhibition preferentially targets the proliferation of leukemic cells. Blood. 2009;114: Copyright 2014 Clinical Care Options, LLC. All rights reserved. 12

13 16. Maertens J, Lübbert M, Fiedler W, et al. Phase I/II study of volasertib (BI 6727), an intravenous polo-like kinase (Plk) inhibitor, in patients with acute myeloid leukemia (AML): results from the randomized phase II part for volasertib in combination with low-dose cytarabine (LDAC) versus LDAC monotherapy in patients with previously untreated AML ineligible for intensive treatment. Program and abstracts of the 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, Georgia. Abstract ClinicalTrials.gov. Volasertib in combination with low-dose cytarabine in patients aged 65 years and above with previously untreated acute myeloid leukaemia, who are ineligible for intensive remission induction therapy (POLO-AML-2). Available at: Accessed May 13, Fontanelli G, Rocco M, Caracciolo F, et al. Sorafenib as monotherapy or in association with cytarabine and clofarabine for the treatment of relapsed/refractory FLT3 ITD-positive advanced acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2014;14:e13-e Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013;121: Cortes JE, Tallman MS, Schiller G, et al. Results of a phase 2 randomized, open-label, study of lower doses of quizartinib (AC220; ASP2689) in subjects with FLT3-ITD positive relapsed or refractory acute myeloid leukemia (AML). Program and abstracts of the 55th American Society of Hematology Annual Meeting and Exposition; December 7-10, 2013; New Orleans, Louisiana. Abstract ClinicalTrials.gov. A phase 3 open-label randomized study of quizartinib (AC220) monotherapy versus salvage chemotherapy in subjects with feline McDonough sarcoma (FMS)-like tyrosine kinase 3 - internal tandem duplication (FLT3-ITD) positive acute myeloid leukemia (AML) refractory to or relapsed after first-line treatment with or without hematopoietic stem cell transplantation (HSCT) consolidation. Available at: Accessed May 13, Smith CC, Lasater EA, Lin KC, et al. Crenolanib is a selective type I pan-flt3 inhibitor. Proc Natl Acad Sci U S A. 2014;111: ClinicalTrials.gov. A phase II study of crenolanib besylate in subjects with relapsed/refractory acute myeloid leukemia with FLT3 activating mutations. Available at: Accessed May 13, Kantarjian H, Jabbour E, Yee K, et al. First clinical results of a randomized phase 2 study of SGI- 110, a novel subcutaneous (SQ) hypomethylating agent (HMA), in adult patients with acute myeloid leukemia (AML). Program and abstracts of the 55th American Society of Hematology Annual Meeting and Exposition; December 7-10, 2013; New Orleans, Louisiana. Abstract 497. Copyright 2014 Clinical Care Options, LLC. All rights reserved. 13