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

Authors:
Smith GiriFrom the Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; and Department of Internal Medicine, Creighton University Medical Center, and Department of Internal Medicine, Division of Hematology and Oncology, University of Nebraska Medical Center, Omaha, Nebraska.

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Shadi HamdehFrom the Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; and Department of Internal Medicine, Creighton University Medical Center, and Department of Internal Medicine, Division of Hematology and Oncology, University of Nebraska Medical Center, Omaha, Nebraska.

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Vijaya Raj BhattFrom the Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; and Department of Internal Medicine, Creighton University Medical Center, and Department of Internal Medicine, Division of Hematology and Oncology, University of Nebraska Medical Center, Omaha, Nebraska.

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James K. SchwarzFrom the Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; and Department of Internal Medicine, Creighton University Medical Center, and Department of Internal Medicine, Division of Hematology and Oncology, University of Nebraska Medical Center, Omaha, Nebraska.

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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.

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).™ Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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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

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 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 intermediate-dose 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

Table 1

Hemogram Results During Different Stages of Disease

Table 1
induction chemotherapy well, experiencing grade 1 skin rash, grade 1 transaminitis, and one episode of neutropenic fever. However, he presented 2 weeks after discharge with pleuritic chest pain and was found to have pulmonary embolism. This was managed with outpatient therapy with enoxaparin. The patient subsequently received one cycle of consolidation therapy with cytarabine, 0.75 g/m2/d for 3 days; idarubicin, 8 mg/m2/d for 2 days; and sorafenib, 400 mg twice daily for 28 days.8 This was complicated by prolonged myelosuppression, sepsis, clostridium difficile infection, weakness, and anorexia. On recovery, the patient was maintained on single-agent sorafenib, 400 mg twice daily,8 which was well tolerated. Seven months after the first relapse, he experienced disease relapse with elevation of his WBC count to 110,000/mcL with 93% blasts. At this point, he was started on hydroxyurea, low-dose cytarabine, and sorafenib, 400 mg twice daily. The patient expired 3 months after his second relapse and 17 months after his initial diagnosis.

Discussion

The presence of an FLT3-ITD mutation in AML has been associated with higher rates of relapse and shorter disease-free and overall survivals.9 A previous study had reported a relapse rate of 74% and a 5-year overall survival rate of 32% in individuals with these mutations.10 The outcomes are significantly worse in patients with FLT3-mutated AML with relapsed disease, advanced age, or poor performance status. However, in patients with NPM1-mutated AML, the presence of low-allelic burden FLT3-ITD mutation, compared with wild-type FLT3, does not confer poor outcomes.11 Although this patient had an NPM1 mutation, the allelic burden of the FLT3-ITD mutation was not available. Increasing recognition of the FLT3-ITD mutation as an adverse prognostic factor in patients with AML has led to the development of potent tyrosine kinase inhibitors targeting this mutation. Several FLT3 inhibitors, such as sorafenib, quizartinib, crenolanib, midostaurin, lestaurtinib, sunitinib, and tandutinib, have shown promising results in these subgroups of patients.5 Limited phase I/II studies on the different FLT3 inhibitors have suggested a potential benefit of these agents; however, benefits had a short duration in most of these studies.8,1216 The long-term utility of these agents has been hampered by the development of drug resistance. Possible mechanisms of drug resistance include point mutations in the FLT3 tyrosine kinase domain, upregulation of the antiapoptotic protein MCL-1, or constitutive activation of FLT3.17 Newer-generation FLT3-ITD inhibitors may be effective in these patients. Newer agents such as crenolanib and quizartinib, individually or in combination with sorafenib, have been shown to be useful in such resistant cases.1820 Similarly, ponatinib is a multikinase inhibitor that has been shown to be effective in cases of acquired FLT3 tyrosine kinase domain mutations.21,22

Sorafenib has been tested in patients with AML both as a monotherapy and in combination with other chemotherapies (Table 2). Pratz et al23 conducted a phase I dose-escalation trial evaluating sorafenib as a monotherapy in relapsed/refractory advanced leukemia. Although marked FLT3-ITD inhibition was achieved, the clinical response was only modest, with 11 of 15 patients experiencing stable disease as the best response. Metzelder et al6 studied the compassionate use of sorafenib among 6 cases of patients with relapsed/refractory FLT3-ITD–mutated AML before and after alloSCT. Sorafenib induced clinically meaningful responses (ranging from a hematologic response to complete remission) in 100% of patients. Similarly, Zhang et al7 reported a clinical response in all 6 patients, who carried solely an FLT3-ITD mutation. A marked reduction in median percentage of blasts in peripheral blood and bone marrow was reported after initiating sorafenib monotherapy in these patients (reduction from 81% to 7% in peripheral blood, and from 75% to 34% in bone marrow, respectively).7 Similarly, a phase I dose-escalation study of sorafenib monotherapy in patients with refractory/relapsed acute leukemia showed complete remission in 5 of 50 patients (10%), but in all patients (100%) with FLT3-ITD mutations.24 Hence, sorafenib has single-agent activity in patients with relapsed/refractory AML with FLT3-ITD mutations.

Few studies have investigated the role of sorafenib in combination with chemotherapy in patients with AML. Inaba et al25 conducted a phase I pharmacokinetic and pharmacodynamic study of sorafenib in combination with clofarabine and cytarabine in pediatric relapsed/refractory leukemia. Overall response was seen in 9 of 11 patients (82%), but in all 5 patients with FLT3-ITD mutations (100%). A dose of 150 mg/m2 seemed to be safer than a dose of 200 mg/m2, with no dose-limiting toxicities noted with the former dosing. In a phase I/II study of sorafenib in combination with cytarabine and idarubicin (regimen used in this case report), a complete remission rate of 75% and 93% was achieved among the entire cohort and patients with FLT3-mutated AML. This resulted in the probability of survival of 74% at 1 year, thus suggesting a high response rate with the combination of sorafenib with chemotherapy in patients with FLT3-mutated AML.8 Another phase I/II study of sorafenib in combination with low-dose cytarabine in older patients, otherwise unsuitable for intensive chemotherapy, showed an overall response of 10%. This could be explained by underrepresentation of FLT3-ITD mutations in the study population, which was only seen in 3 of 21 patients (14%).26 Another phase II trial tested the combination of azacytidine and sorafenib in 37 patients with refractory/relapsed AML with FLT3-ITD mutations. The overall response rate was 46%, with 64% achieving greater than 85% FLT3 inhibition during the first cycle of chemotherapy.27 A recent randomized controlled trial showed that the addition of sorafenib to cytarabine and daunorubicin is not beneficial among older patients with AML (including in a subgroup with FLT3-ITD mutations). Because the trial included only 28 patients with FLT3-ITD mutations, the study may not have adequate power to detect the difference in outcomes in this subgroup.28

The optimal role of sorafenib in patients with AML remains unanswered. For example, sorafenib monotherapy has not been compared with the combination of sorafenib and chemotherapy in patients with AML and the FLT3-ITD mutation, and therefore the role of combination therapy versus sorafenib monotherapy remains unclear. Despite promising results of sorafenib in these clinical trials, the development of resistance during the course of therapy is a major clinical challenge. Given their short-term efficacy and relatively few adverse effects, these agents seem to be particularly helpful as monotherapy in medically unfit patients with relapsed/refractory AML with FLT3-ITD mutations, who otherwise are poor candidates to receive cytotoxic chemotherapy (because of prior therapy). Thus, in select patients, sorafenib may be used as a bridge to alloSCT.29 The 2015 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML acknowledge the poor prognosis associated with the presence of FLT3-ITD mutations in patients with AML with normal karyotype. Although data are considered inadequate to support the use of sorafenib during induction, it may be considered in relapsed AML. Importantly, NCCN Guidelines recommend clinical trials as the standard therapy for patients with FLT3 abnormalities or other poor prognostic features. (to view the most recent version of these guidelines, visit NCCN.org).30 Conversely, in clinical practice, sorafenib is frequently used as an off-label indication in patients with relapsed/refractory AML with the FLT3-ITD mutation.29

Table 2

Trials of Sorafenib in Patients With Relapsed/Refractory AML

Table 2

The present patient received initial standard chemotherapy with cytarabine and daunorubicin, followed by azacytidine. Although this patient was a potential candidate for alloSCT, he declined this option. Relapse at 10 months was managed with sorafenib in combination with cytarabine and idarubicin, followed by consolidation therapy and sorafenib maintenance, which resulted in disease control for 7 months. The response duration of 7 months in an older patient with relapsed AML and the FLT3-ITD mutation indicates a good response to the sorafenib-based therapy. This patient was able to tolerate induction therapy without major toxicity but developed complications during consolidation therapy. Hence, he was maintained on single-agent sorafenib. Several studies discussed previously68,25 demonstrated a role for sorafenib in patients with relapsed/refractory AML and the FLT3-ITD mutation. Sorafenib monotherapy is often easily tolerated, even by heavily pretreated older patients,6,7,23,24 as illustrated in this case. Hence, it can be used as a palliative option or a bridge to alloSCT in eligible patients.29 Larger phase II/III trials are indicated to compare the outcomes of sorafenib monotherapy versus its combination with chemotherapy in patients with relapsed/refractory AML with the FLT3-ITD mutation. Future studies should also focus on management of AML in patients who develop resistance to first-line FLT3 inhibitors.

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.

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.

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Correspondence: Vijaya Raj Bhatt, MBBS, University of Nebraska Medical Center, Department of Internal Medicine, Division of Hematology-Oncology, 987680 Nebraska Medical Center, Omaha, NE 68198-7680. E-mail: vijaya.bhatt@unmc.edu

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