Sorafenib in Relapsed AML With FMS-Like Receptor Tyrosine Kinase-3 Internal Tandem Duplication Mutation

Old age (≤65 years), relapsed or refractory disease, and the presence of FMS-like receptor tyrosine kinase-3 (FLT3) internal tandem duplication (ITD) mutation are poor prognostic factors in acute myeloid leukemia (AML). FLT3 inhibitors such as sorafenib have been shown to have a potential role in treating relapsed or refractory AML with FLT3 mutations. In the present report, the use of sorafenib in combination with cytarabine and idarubicin resulted in disease control for 7 months in an older patient with relapsed FLT3-positive AML. This case report and the existing literature indicate that sorafenib has disease activity against relapsed AML with the FLT3-ITD mutation in older patients. Larger multicenter studies should be conducted to confirm these findings, which have the potential to improve outcomes in this high-risk AML subgroup. (J Natl Compr Canc Netw 2015;13:508–514) NCCN: Continuing Education Accreditation Statement This activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians. NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center`s Commission on Accreditation. This activity is accredited for 1.0 contact hours. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity. All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/ node/65994; and 4) view/print certificate. Release date: May 13, 2015; Expiration date: May 13, 2016 Learning Objectives Upon completion of this activity, participants will be able to: • Describe the factors associated with poor prognosis for patients with AML • Discuss the potential benefits of the use of several therapies to treat patients with FLT3-ITD mutations From the aDepartment of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; and bDepartment of Internal Medicine, Creighton University Medical Center, and cDepartment of Internal Medicine, Division of Hematology and Oncology, University of Nebraska Medical Center, Omaha, Nebraska. Submitted July 7, 2014; accepted for publication October 2, 2014. The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. Correspondence: Vijaya Raj Bhatt, MBBS, University of Nebraska Medical Center, Department of Internal Medicine, Division of HematologyOncology, 987680 Nebraska Medical Center, Omaha, NE 68198-7680. E-mail: vijaya.bhatt@unmc.edu EDITOR Kerrin M. Green, MA, Assistant Managing Editor, JNCCN—Journal of the National Comprehensive Cancer Network Ms. Green has disclosed that she has no relevant financial relationships. CE AUTHORS Deborah J. Moonan, RN, BSN, Director, Continuing Education, has disclosed that she has no relevant financial relationships. Ann Gianola, MA, Manager, Continuing Education Accreditation & Program Operations, has disclosed that she has no relevant financial relationships. Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations, has disclosed that she has no relevant financial relationships. Rashmi Kumar, PhD, Senior Manager, Clinical Content, has disclosed that she has no relevant financial relationships. Courtney Smith, PhD, Oncology Scientist/Medical Writer, has disclosed that she has no relevant financial relationships. Molecular Insights in Patient Care Sorafenib in Relapsed AML © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 13 Number 5 | May 2015 509 C E smoking or drinking alcohol. Physical examination revealed a blood pressure reading of 130/70 mm Hg, heart rate of 77 beats per minute, temperature of 98.6oF, respiratory rate of 18 breaths per minute, and oxygen saturation of 96%. He had bilateral calf tenderness without erythema or edema. The remainder of the examination was unremarkable. Laboratory evaluation revealed a WBC count of 59,000/mcL with 93% blasts, hemoglobin level of 9.2 g/dL, platelet count of 83,000/mcL (Table 1), and normal glucose and electrolyte levels, coagulation profile, and renal and liver function tests. Bone marrow biopsy revealed blasts with high nuclear-to-cytoplasmic ratio, occasional nucleoli, and some folded or bilobed nuclei. Most blasts appeared agranular; however, rare cytoplasmic granules and Auer rods were seen. Blasts expressed CD33, CD45, partial CD38, partial CD71, partial CD117, and cytoplasmic myeloperoxidase, consistent with AML. The blasts were negative for CD34, HLA-DR, terminal deoxynucleotidyl transferase, and lymphoid markers. Cytogenetics demonstrated normal male chromosomes, 46,XY[20]. Fluorescence in situ hybridization was negative for t(15;17) translocation. Deoxyribonucleic acid amplification showed FLT-ITD and NPM1 mutations. The patient received induction chemotherapy with 7-day infusional cytarabine (100 mg/m2/d) and 3-day daunorubicin (60 mg/m2/d). A repeat bone marrow biopsy at day 14 demonstrated residual leukemia with 15% blasts. After a lengthy discussion regarding different options, including alloSCT in the future, the patient chose to be treated with low-intensity therapy. Hence, he was started on subcutaneous azacytidine (75 mg/m2/d for 7 days) with a repeat cycle every 4 weeks. The patient received 9 cycles of azacytidine, and showed an improvement in his hemogram. Ten months after his first presentation, the patient presented with dyspepsia and was feeling unwell. His CBC count was 20,700/mcL with 80% blasts. The patient was started on intermediatedose cytarabine (1.5 g/m2/d for 3 days), idarubicin (12 mg/m2/d for 3 days), and sorafenib (400 mg twice daily for 7 days).8 The patient also received prophylactic filgrastim and prophylactic antibiotic, antifungal, and antiviral agents. A repeat bone marrow biopsy at day 28 showed 50% cellularity and 5% blasts. Cytogenetics demonstrated normal male chromosomes, 46,XY[19]. The patient tolerated Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults, with an estimated incidence of 3 cases per 100,000 people.1 Factors associated with poor prognosis include advanced age, unfavorable cytogenetics, molecular markers (such as FMS-like receptor tyrosine kinase-3 [FLT3], internal tandem duplication [ITD] mutation, or absence of nucleophosmin [NPM1] mutation), poor performance status, multiple comorbidities, inability to tolerate chemotherapy, and multidrug resistance.2 The management of patients with relapsed/refractory AML remains a huge clinical challenge with few therapeutic options available, particularly for older patients.3 Among the intermediate cytogenetic risk group with normal karyotype, the FLT3-ITD mutation portends poor disease-free and overall survivals.4 FLT3 is normally expressed on the surface of hematopoietic stem cells and is important in the normal development of pluripotent stem cells.5 FLT3 is mutated in approximately one-third of AML cases.4 Therapeutic options in cases of refractory or relapsed FLT3-positive AML are limited, particularly in the presence of poor performance status or prior allogenic stem cell transplantation (alloSCT).3 FLT3 inhibitors, such as sorafenib, may have some role in these situations.6 Sorafenib was initially designed as a small molecule inhibitor of c-Raf kinase but has demonstrated efficacy in inhibiting the activities of FLT3, vascular endothelial growth factor receptors 2 and 3, and members of the platelet-derived growth factor receptor family.7 This report presents a case of an older man with relapsed FLT3-positive AML who experienced disease control for 7 months with the combination of chemotherapy and sorafenib. Case Presentation A 65-year-old man presented to the emergency room who had experienced worsening pain in both calves during the past 2 to 3 weeks, fever and chills for 1 week, rectal bleeding, and weight loss. His past medical history was significant for prostate adenocarcinoma (Gleason 7) treated 4 years ago with intensity-modulated radiation therapy (8000 cGy in 40 fractions), diabetes mellitus, hypertension, hyperlipidemia, atrial fibrillation, gastroesophageal reflux disease complicated by Barrett esophagus, and glaucoma. Family history was significant for head and neck cancer in his father. The patient denied Molecular Insights in Patient Care