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Review
Allogeneic stem cell transplantation and targeted therapy for FLT3/ITD+ acute myeloid leukemia: an update Expert Rev. Hematol. 7(2), 301–315 (2014)
Bei Hu1, Praveen Vikas2, Mohamad Mohty3–5 and Bipin N Savani*6 1 Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA 2 University of Iowa Health Care, UI Medical Oncology and Hematology, McCreery Cancer Center, Ottumwa, IA, USA 3 Hematology Department, Hopital Saint-Antoine Hospital, AP-HP, Paris, France 4 INSERM UMRs 938, Paris, France 5 Universite´ Pierre et Marie Curie, Paris, France 6 Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Section of Hematology and Stem Cell Transplantation, Division of Hematology/ Oncology, 1301 Medical Center Drive, 3927 TVC Nashville, TN-37232, USA *Author for correspondence: Tel.: +1 615 936 038 Fax: +1 615 936 1812 [email protected]
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Survival of patients with acute myelogenous leukemia (AML), particularly in younger patients, has improved in recent years due to improved understanding of disease biology, post remission therapies and supportive care. AML, however, remains difficult to treat as many patients will still ultimately relapse and die of their disease. This is particularly true in AML patients with identified FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) molecular mutations, which typically confers a poor prognosis. The FLT3-ITD mutation occurs in about one-quarter of patients diagnosed with AML. Oftentimes, these patients are referred for early allogeneic hematopoietic stem cell transplantation (HSCT) in hopes of overcoming this poor prognostic factor. Several studies have demonstrated some benefit with HSCT in patients with FLT3-ITD mutation. However, recent data suggested that FLT3-ITD mutation remains a poor prognostic factor even after early HSCT; these patients remain at risk for early relapse after transplantation, emphasizing ongoing efforts to explore maintenance therapy with FLT3-ITD inhibitors in the post-transplant setting. KEYWORDS: drug resistance • FLT3 AML • hematopoietic stem cell transplantation • improving outcomes • tyrosine kinase inhibitors
Acute myeloid leukemia (AML) is the most common form of acute leukemia in the adult population with over 10,000 people diagnosed in the USA each year [1]. It is a heterogenous hematologic malignancy and often associated with karyotypic and molecular abnormalities which are used as prognostic indicators for risk of relapse and responsiveness to chemotherapy [2]. FMS-like tyrosine kinase 3 (FLT3) mutations are one of the most common molecular abnormalities, present in 20–46% of all AML cases [3–8]. FLT3 is normally expressed in hematopoietic stem cells and its expression is lost as stem cells differentiate. FLT3 ligand in combination with other growth factors causes proliferation of hematopoietic stem cells [9]. FLT3 mutations cause autophosphorylation as well as activation of multiple downstream signaling pathways, including the Ras/MAPK kinase (MEK), PI3K/Akt and STAT5 pathways [9–12]. Autophosphorylation and activation of these pathways ultimately results in increased 10.1586/17474086.2014.857596
proliferation and reduced susceptibility to apoptosis in hematopoietic cells [13–15]. Thus, FLT3 AML is often associated with increased white blood cell counts and high percentage of blasts in the peripheral blood and bone marrow [5,16]. Two major classes of activating FLT3 mutations have been discovered: internal tandem duplications (ITD) which occurs in 30% of cases and tyrosine kinase domain mutations (TKD) which are present in 10% of cases [17,18]. Compared with patients with wild-type FLT3, those with the FLT3-ITD mutation, have shorter remissions and worse survival outcomes [3,17,19]. However, the prognostic impact of FLT3-TKD mutations is more controversial as some studies reported decreased overall survival (OS) and shorter remissions [3,19–21] while others not only demonstrated no impact on prognosis [4,22,23] but even showed a favorable prognosis [24]. Over the years, multiple strategies have been employed to overcome the adverse prognosis
2014 Informa UK Ltd
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associated with FLT3 mutations, with mixed outcomes at best. In this article, we reviewed the effectiveness of hematopoietic stem cell transplantation (HSCT) and tyrosine kinase inhibitors (TKIs), in the treatment of FLT3 AML.
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Efficacy of transplantation for FLT3-ITD AML
When treated with chemotherapy alone, patients with FLT3-ITD AML have a higher rate of relapse compared with their FLT3 wild-type counterparts [3,17,25–27]. While HSCT, during the first complete remission (CR1), has been offered to patients as a therapeutic approach in hopes of overcoming the poor prognostic feature associated with the FLT3-ITD mutation, there have been no randomized clinical trials to demonstrate that HSCT improves overall outcomes. However, multiple retrospective studies have been conducted to evaluate the role of transplant in the treatment of FLT3-ITD+ AML (TABLE 1). A retrospective analysis of 1135 patients showed that FLT3-ITD+ AML was associated with increased relapse even in those who underwent a transplant [28]. Although the study showed decreased relapsed rate in patients with FLT3-ITD+ AML undergoing allograft, there was no difference in OS. The authors of the study, therefore, concluded that the presence of the FLT3 mutation should not affect the decision for transplant. However, those who criticized the interpretation of the study noted that there was no comparison of the outcomes of those who received chemotherapy only versus those who received an allograft [29]. The data showed that the relapse rate for the chemotherapy group was 89% while that of the allograft group was 50% with a relative hazard ratio of 5.9. Additionally, the OS of the chemotherapy group was 8% while that of the allograft group was 43% with a relative hazard ratio of 3.0. Critics of the study also performed an analysis of FLT3-ITD+ AML patients and demonstrated that those who received an autograft had an improved survival over the nontransplanted patients (48 vs 8%, p < 0.05) [29]. However, the original authors of the study contested that the baseline characteristics of the patients who received an autograft were different than those who did not and required cautious interpretation of the data. While outcomes appeared improved in transplant recipients, this discourse demonstrated the need for a prospective, randomized trial comparing outcomes of transplant versus chemotherapy only in patients with FLT3-ITD+ AML while controlling for various baseline patient characteristics which may prove to be difficult to perform in practice. A European group also reported findings in which FLT3-ITD mutation remained a negative prognostic factor even after transplantation [30]. They performed a retrospective analysis with 206 patients with AML who underwent HSCT in CR1. Patients with the FLT3-ITD mutation had a higher relapse incidence at 2 years and a lower disease free survival (DFS) when compared with FLT3 wild-type patients. However, patients with the FLT3-ITD mutation had a better 2-year DFS compared to those who received chemotherapy alone, although the authors acknowledged that selection bias could not be ruled out given that patients 302
who relapsed prior to transplant were excluded from the analysis [30]. Another retrospective study conducted at Vanderbilt University with 79 patients with AML in CR1 who had undergone allogeneic transplantation also confirmed that FLT3-ITD mutation portends a poor prognosis as these patients had a significantly inferior DFS, increased risk of relapse and a trend toward decreased OS [31]. However, there was no comparison of patients with FLT3-ITD+ AML who had undergone only chemotherapy versus those who proceeded to transplant. While the study showed that patients with the FLT3-ITD mutation who underwent transplantation had a low OS, it is unclear if those with FLT3-ITD+ AML who had only undergone consolidation chemotherapy would have had an even worse prognosis. On the other hand, a number of studies demonstrated HSCT to be beneficial for AML patients with FLT3-ITD mutation. A study conducted in Germany was performed on 376 patients who were treated based on the following protocol: patients with a matched sibling donor underwent allogeneic transplantation; those who did not have a matched donor underwent autologous transplantation; and those whose stem cells could not be successfully mobilized, were treated with standard consolidation chemotherapy. The results showed that in patients who underwent autologous or allogeneic transplant, OS was comparable between the FLT3-ITD mutation group and the FLT3 wild-type group, suggesting that transplantation may overcome the negative prognostic factor associated with FLT3-ITD mutation [32]. In contrast, FLT3-ITD+ patients who underwent chemotherapy alone had an inferior probability of survival and a higher probability of relapse when compared to their wild-type counterparts. However, the paper did not elaborate if there were any confounding characteristics of the patients who received chemotherapy alone (i.e., multiple comorbidities, older age, etc.). A retrospective study conducted in Japan also showed similar results. Thirty-four patients with AML were treated with chemotherapy followed by autologous transplantation with similar 5 year DFS and OS in both FLT3-ITD+ and FLT3 wild-type patients [33]. In another study conducted in Italy, 73 patients (22% with FLT3-ITD mutations) with mostly newly diagnosed AML underwent autologous stem cell transplantation following induction and consolidation chemotherapy [34]. OS and DFS were similar between patients with the FLT3 mutation and their wild-type counterparts. The authors of the study did acknowledge that transplanted patients were specifically selected for best response to induction, consolidation and mobilization and that those who relapsed early during consolidation or while waiting for transplant were excluded from analysis. Comparable results were seen in a retrospective analysis with 133 newly diagnosed AML patients under the age of 60 years (23% with FLT3-ITD mutation) at Johns Hopkins in which median survival in patients with FLT3-ITD mutation was similar to that of the entire cohort and that of FLT3 wild-type patients. They theorized that OS was similar in the two groups Expert Rev. Hematol. 7(2), (2014)
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1153
206
79
999
34
73
133
37
Gale et al. (2005)
Brunet et al. (2012)
Sengsayadeth et al. (2012)
Bornhauser et al. (2007)
Yoshimoto et al. (2005)
Palmieri et al. (2007)
Dezern et al. (2011)
Singh et al. (2011)
FLT3+ AML patient undergoing consolidation chemotherapy versus auto-sct
FLT3+ versus wild type AML undergoing allo-sct if they had a match, those without a match underwent consolidation chemotherapy
FLT3+ versus wild type AML undergoing auto-sct after induction and consolidation chemotherapy
FLT3+ versus wild type AML undergoing auto-sct and high dose chemotherapy
FLT3+ versus wild type AML undergoing auto-sct, allo-sct, versus consolidation chemotherapy
FLT3+ versus wild type AML in CR1 undergoing allo-sct
FLT3+ AML versus wild type AML undergoing allo-sct in CR1
FLT3-ITD+ AML versus FLT3 wild type AML undergoing auto-sct, allo-sct or chemotherapy
Design
[31]
[32]
[33]
[34]
[35]
[36]
OS between FLT3+ and wild-type were not different in the auto-sct or allo-sct. FLT3+ AML patients who received chemotherapy had lower probability of survival and increased risk of relapse OS and disease free survival were similar between patients with or without FLT3 mutation suggesting that transplant may overcome the poor prognosis associated with FLT3+ AML OS and disease free survival were similar between patients despite FLT3 status suggesting that transplant may overcome the adverse prognosis associated with FLT3+ AML Median OS of FLT3 AML patient was comparable to that of the entire cohort (19.3 vs 15.5 months)
FLT3-ITD patients who underwent an auto-sct in CR1 had improved disease free survival but similar OS when compared to those who received only consolidation therapy
[30]
[28]
Ref.
Patients with FLT3+ AML had inferior DFS (2 year DFS 19 vs 64%, p = 0.0027), increased risk of relapse (1 year: 59 vs 19%, p = 0.01), and trend towards decreased overall survival (p = 0.08) compared to those without the mutation
FLT3+ AML patients had shorter interval from CR to transplantation, higher relapse incidence, lower leukemia-free survival and higher number of chemotherapy courses before reaching CR
FLT3+ AML patients who underwent transplant had an increased relapse compared to wild type counterparts
Summary of results
AML: Acute myeloid leukemia; CR: Complete remission; DFS: Disease-free survival; FLT3: FMS-like tyrosine kinase 3; OS: Overall survival.
Patients (n)
Study (year)
Table 1. Transplantation outcome in FLT3+ AML.
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Management of FLT3 AML: an update
Review
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Review
Hu, Vikas, Mohty & Savani
because of their institution’s policy of aggressively pursuing allogeneic transplantation during CR1 [35]. In an analysis conducted by Schlenk et al., with 872 adult patients with cytogenetically normal AML in which 150 underwent allogeneic transplant for consolidation therapy because of the availability of a matched related donor, benefit of transplant was limited to the subgroup of patients with FLT3-ITD+ or wild-type NPM1+CEBPA without FLT3-ITD [4]. Finally, a retrospective analysis at Harvard University compared autologous stem cell transplantation versus consolidation chemotherapy in 37 adult patients below the age of 60 years with newly diagnosed normal karyotype FLT3-ITD+ AML. Their analysis showed that patients with FLT3-ITD mutation who underwent an autologous stem cell transplant in CR1 had an improved DFS but similar OS when compared to those who received consolidation chemotherapy [36]. While the decision to proceed transplant remains controversial, given the poor prognosis with chemotherapy alone, there has been a trend to offer transplantation despite the studies showing conflicting results [37–39]. For the very least, one study showed that when allogeneic transplantation was performed early during CR1, the survival of young patients with FLT3-ITD+ AML was improved [40]. Current targeted therapy for FLT3 AML
More recently, given the success of TKIs in the treatment of chronic myelogenous leukemia [41,42], much interest has been generated around targeted therapy in the treatment of FLT3-ITD+ AML. TKIs inhibit FLT3, thereby blocking the altered signaling pathway that contributes to the uncontrolled cell proliferation [43]. While many of the TKIs studied are capable of inhibiting both mutant-FLT3 and wild-type FLT3 autophosphorylation, more cytotoxicity was detected in the mutated FLT3 cell lines [44]. Thus, due to their antitumor effects in preclinical trials, TKIs have been investigated in multiple trials to determine their efficacy as a single agent and in combination with other therapies in newly diagnosed, relapsed and refractory populations with FLT3-ITD+ AML (TABLE 2) [45,46]. Currently, preclinical trials show that TKIs combined with chemotherapy in a sequence-specific order exhibit synergistic apoptosis of leukemic cells in vitro [47]. TKI used simultaneously or immediately following chemotherapy produced synergistic cytotoxicity. Antagonism was observed when the TKI was used prior to the chemotherapy. Sorafenib
Sorafenib (BAY 43-9006), an oral multikinase inhibitor [48], approved for use for advanced hepatocellular carcinoma and renal cell carcinoma [49,50], has been the center of multiple clinical trials as targeting therapy against FLT3-ITD+ AML. Sorafenib has been shown to effectively suppress FLT3 autophosphorylation leading to apoptosis of leukemic cells [45,46]. It has also been found to be safe and efficacious in three Phase I trials in patients with refractory or relapsed AML [51–53]. In two 304
of the trials, a decrease in peripheral blasts was noted but the response was transient [51,53]. In the last trial, while no patients achieved complete or partial response, 73% had stable disease and 40% showed a reduction in bone marrow blasts after one cycle. In this trial, sorafenib 400 mg twice daily (b.i.d.) for 21 days was found to be the maximally tolerated dose (MTD) and 55% experienced grade 3 or greater toxicity with the most common being hypokalemia (13%) and fatigue (16%) [52]. In one case report of FLT3-ITD+ AML, molecular remission was induced by sorafenib after allogeneic HSCT [54]. In another case report, the patient was treated with sorafenib for refractory FLT3-ITD+ AML. Although the patient eventually relapsed again and died 22 months after initial diagnosis, FLT3-ITD mutation was no longer detected during sorafenib treatment or at the time of final relapse [55] suggesting that another mechanism other than FLT3 mutation was responsible for the relapse. Sorafenib has also been studied in combination with chemotherapy. In one trial, 10 patients with relapsed AML and 51 patients with untreated AML were treated with both sorafenib and chemotherapy (cytarabine 1.5 g/m2 and idarubicin 12 mg/m2). Seventy five percent achieved a CR including all 15 patients with mutated FLT3-ITD AML although one of the patients experienced CR with incomplete platelet recovery [56]. Only 66% of patients, without the FLT3 mutation, were able to achieve CR. The overall probability of survival at 1 year was 74%. Among the 15 patients with FLT3-ITD AML, 10 relapsed and five remained in CR with a median follow-up of 62 weeks. This trial showed that sorafenib can be safely used in combination with chemotherapy and can achieve a high rate of CR in FLT3-ITD AML. Another trial showed 100% CR in 18 FLT3-ITD+ AML patients who received sorafenib in combination with idarubicin and cytarabine chemotherapy [57]. Median CR duration was 8.8 months and at a median followup of 9 months, 55% had relapsed. DNA sequencing demonstrated no evidence of an acquired FLT3 point mutation at the time of relapse, suggesting that other mechanisms of sorafenib resistance might play a role. A second clinical trial from MD Anderson demonstrated that 5-azacytidine and sorafenib resulted in a response rate of 46% in 37 patients with relapsed or refractory AML [58]. Ninety three percent of patients had a FLT3-ITD mutation; 64% of patients achieved greater than 85% FLT3 inhibition during cycle one of therapy. Median duration of remission was 2.3 months. While the initial high response rate is likely due to a high percentage (64%) of patients achieving adequate FLT3 inhibition, the short time to relapse could be due to the development of drug resistance to sorafenib. In contrast, in a multicenter, randomized, placebo-controlled, double-blind, Phase II trial of 201 elderly (>60 years) patients with AML who received standard 7 + 3 induction chemotherapy with cytarabine and daunorubicin plus two cycles of consolidation therapy with intermediate dose (6 1 g/m2) of cytarabine, sorafenib had no effect on event-free survival (EFS) or OS compared to placebo when given between the cycles and after chemotherapy. However, only 14% of the patients in the Expert Rev. Hematol. 7(2), (2014)
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FLT3, c-KIT, VEGF, NRAS, Raf, PDGF Suppresses FLT3 autophosphorylation and downstream signaling, promotes apoptosis
Phase I/II
Phase I/II/III
Phase IB Phase II
Sorafenib/Bay 43-9006/ Nexavar
Midostaurin/ PKC412
Lestaurtinib/ CEP701
Safe GI effects: 29% Diarrhea: 38% Anemia: 27% Thrombocytopenia: 23%
GI effects: 60–83% Diarrhea: 68% Myleosuppression: 15–18%
Nausea/vomiting, generalized weakness, infection
2.8 100.nM (400 mg, b.i.d.)
10 nM (50–100 mg, b.i.d.)
2–5 nM 40–80 mg b.i.d
Idarubicin and cytarabine: CR + CRP: 75–100% 5-azacytidine: response rate: 46% HSCT: 0–33% CR
Daunorubicin, cytarabine: CR:74% CDDO-Me, HG-7-85-01 and HG-7-86-01, synergistically induces apoptosis in FLT-ITD mutant Salvage chemotherapy: Mitoxantrone Etoposide Cytarabine: CR + CRp: 29%
Peripheral blood: 70% Bone marrow: 25%
CR: 0% Peripheral blood: 0–60% Bone marrow: 0–5%
Side effects
Peripheral blood: 38–73% Bone marrow: 8–66% Resistant: 47%, D835/I386, Y842C mutation [103]
FLT3 IC50(nM) (clinical doses)
Combination with
Clinical response (%)
IC50 refers to the concentration required for the inhibition of FLT3 autophosphorylation. AML: Acute myeloid leukemia; b.i.d.: Twice daily; CR: Complete remission; FLT3-ITD: FMS-like tyrosine kinase 3-internal tandem duplications; GI: Gastrointestinal.
FLT3, TrK A/B/C, VEGFR, STAT5, JAK2, ERK. Inhibits phosphorylation of FLT3, competitively inhibits ATP binding to the Trk kinase domain
FLT3, c-kit, VEGFR-2, PDGFR a and b Suppresses FLT3 autophosphorylation and induces apoptosis in AML
Targets and mechanism
Clinical trial
Inhibitor
Table 2. Published data on FMS-like tyrosine kinase 3 inhibitors.
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[45,46, 48–65,
• Decrease in peripheral blasts but transient responses • Mixed results when combined with transplantation, one study showed synergistic effect with transplant • Combined with cytarbine and idarubicin led to high rates of CR (75–80%)
[74–77]
[66–69]
• High CR rates when combined with chemotherapy in FLT3 AML • A majority of patients (>70%) achieved reduction in bone marrow or peripheral blasts • 36–60% of patients had reductions in bone marrow and peripheral blasts but responses were transient • When combined with chemotherapy, no difference in response between the lestaurtinib group and the control group • The lestaurtinib group was associated with more adverse events, that is, infections • No survival benefit
103,105]
Ref.
Summary
Management of FLT3 AML: an update
Review
305
306
Phase I/II
Phase I/II
Phase I/II
Sunitinib/ SU11248
Tandutinib/ MLN518
KW-2449
FLT3, kit, PDGFR-a, SRC, ABL, aurora kinase. Induces the reduction of phosphorylated histone H3, downregulates FLT3/STAT5, resulting in G1-2/M arrest and apoptosis
FLT3, c-KIT, PDGFR b
FLT3, KIT, VEGFR, PDGFR a and b, RET, CSF-1R Inhibits FLT3-driven phosphorylation and induces apoptosis, inhibits FLT3-induced VEGF production
Targets and mechanism
GI effects, muscular weakness, fatigue
GI effects
30–200 nM 50–700 mg
13 nM 100 mg b.i.d
45% of FLT3-ITD+ patients achieved greater than 50% reduction in peripheral blasts
Cytarabine and daunorubicin produce synergistic antiproliferative effects on FLT3-ITD+ cells in preclinical trial
Mucositis, myelosuppression, bleeding, infection, Diarrhea: 10% Nausea: 10%
50 nM 50–200 mg
RAD001(Rapamycin analog) and cytarabine or daunorubicin in preclinical trials
Peripheral blood:100% in FLT3-mutant, 28% in FTL3-WT
0–75% decreases in PB and BM
Side effects
FLT3 IC50(nM) (clinical doses)
Combination with
Clinical response (%)
IC50 refers to the concentration required for the inhibition of FLT3 autophosphorylation. AML: Acute myeloid leukemia; b.i.d.: Twice daily; CR: Complete remission; FLT3-ITD: FMS-like tyrosine kinase 3-internal tandem duplications; GI: Gastrointestinal.
Clinical trial
Inhibitor
Table 2. Published data on FMS-like tyrosine kinase 3 inhibitors (cont.).
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[81,82]
[78–80]
• Decreased peripheral and bone marrow blasts • Synergistic antiproliferative and pro-apoptic effects on FLT3 blasts when combined with standard induction chemotherapy • Unacceptable side effects and low clinical efficacy has limited further development of this drug for use in clinical trials • Inhibits not only in FLT3-ITD but also FLT3/KDM and WTFLT3 overexpressed leukemia cells • Reductions in peripheral blast counts were transient
[70–73]
Ref.
• 100% of FLT3 mutant developed morphologic or partial responses of short duration • Only 20% of FLT-WT responded to sunitinib
Summary
Review Hu, Vikas, Mohty & Savani
Expert Rev. Hematol. 7(2), (2014)
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Phase I/II
Preclinical
Preclinical
Preclinical
Preclinical
Quizartinib/ AC220
VX322
SKLB1028
BPR1J-097
Linifanib/ ABT-869
AKT, GSK3b, FLT3, VEGF. Inhibits phosphorylation of AKT and GSK3b, induces apoptosis
FLT3, STAT. Suppresses phosphorylation of FLT3 and STAT, induces apoptosis
CDK, FLT3, JAK2. Causes antiproliferation and proapoptotic activity in leukemia cell lines and primary blasts
FLT3 and c-KIT, RTKs with enzyme Ki. Inhibits FLT3-ITD and c-KIT mutations
c-KIT, RET, PDGFR, CSF1R, FLT3
Targets and mechanism
0.55–10 nM in FLT3-ITD In cells, 15 mg alone, 10 mg with cytarabine
Fatigue, febrile neutropenia
• Effective FLT3 inhibition in those with the ITD mutation
• Reduces size of tumor and induces apoptosis in MOLM-13 and MV4-11 murine xenograft models
1–10 nM
Inhibit cells proliferation in AML FLT3-ITD better than FLT-WT and AML FLT3negative in cell lines Cytarabine
• Prolongs survival in a disseminated AML model with wildtype FLT3 and JAK2
17–100 nM
Anti-proliferative effects in a broad range of tumor cell lines and induces G1 cell cycle arrest and apoptosis
Decreased FLT3 phosphorylation seen in 100% (3/3) of FLT3-ITD +, 33% (8/24) of WT/D835 TKD/other unknown mutation. Decreased phosphorylation of ERK 28% of patients
• Prolongs survival of FLT3-ITD mutated mice
• Rapid and relatively durable responses up to 67+ weeks (median 12–14 weeks) • Higher response rate in FLT3-ITD
Summary
Review
Allogeneic stem cell transplantation and targeted therapy for FLT3/ITD+ acute myeloid leukemia: an update Expert Rev. Hematol. 7(2), 301–315 (2014)
Bei Hu1, Praveen Vikas2, Mohamad Mohty3–5 and Bipin N Savani*6 1 Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA 2 University of Iowa Health Care, UI Medical Oncology and Hematology, McCreery Cancer Center, Ottumwa, IA, USA 3 Hematology Department, Hopital Saint-Antoine Hospital, AP-HP, Paris, France 4 INSERM UMRs 938, Paris, France 5 Universite´ Pierre et Marie Curie, Paris, France 6 Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Section of Hematology and Stem Cell Transplantation, Division of Hematology/ Oncology, 1301 Medical Center Drive, 3927 TVC Nashville, TN-37232, USA *Author for correspondence: Tel.: +1 615 936 038 Fax: +1 615 936 1812 [email protected]
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Survival of patients with acute myelogenous leukemia (AML), particularly in younger patients, has improved in recent years due to improved understanding of disease biology, post remission therapies and supportive care. AML, however, remains difficult to treat as many patients will still ultimately relapse and die of their disease. This is particularly true in AML patients with identified FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) molecular mutations, which typically confers a poor prognosis. The FLT3-ITD mutation occurs in about one-quarter of patients diagnosed with AML. Oftentimes, these patients are referred for early allogeneic hematopoietic stem cell transplantation (HSCT) in hopes of overcoming this poor prognostic factor. Several studies have demonstrated some benefit with HSCT in patients with FLT3-ITD mutation. However, recent data suggested that FLT3-ITD mutation remains a poor prognostic factor even after early HSCT; these patients remain at risk for early relapse after transplantation, emphasizing ongoing efforts to explore maintenance therapy with FLT3-ITD inhibitors in the post-transplant setting. KEYWORDS: drug resistance • FLT3 AML • hematopoietic stem cell transplantation • improving outcomes • tyrosine kinase inhibitors
Acute myeloid leukemia (AML) is the most common form of acute leukemia in the adult population with over 10,000 people diagnosed in the USA each year [1]. It is a heterogenous hematologic malignancy and often associated with karyotypic and molecular abnormalities which are used as prognostic indicators for risk of relapse and responsiveness to chemotherapy [2]. FMS-like tyrosine kinase 3 (FLT3) mutations are one of the most common molecular abnormalities, present in 20–46% of all AML cases [3–8]. FLT3 is normally expressed in hematopoietic stem cells and its expression is lost as stem cells differentiate. FLT3 ligand in combination with other growth factors causes proliferation of hematopoietic stem cells [9]. FLT3 mutations cause autophosphorylation as well as activation of multiple downstream signaling pathways, including the Ras/MAPK kinase (MEK), PI3K/Akt and STAT5 pathways [9–12]. Autophosphorylation and activation of these pathways ultimately results in increased 10.1586/17474086.2014.857596
proliferation and reduced susceptibility to apoptosis in hematopoietic cells [13–15]. Thus, FLT3 AML is often associated with increased white blood cell counts and high percentage of blasts in the peripheral blood and bone marrow [5,16]. Two major classes of activating FLT3 mutations have been discovered: internal tandem duplications (ITD) which occurs in 30% of cases and tyrosine kinase domain mutations (TKD) which are present in 10% of cases [17,18]. Compared with patients with wild-type FLT3, those with the FLT3-ITD mutation, have shorter remissions and worse survival outcomes [3,17,19]. However, the prognostic impact of FLT3-TKD mutations is more controversial as some studies reported decreased overall survival (OS) and shorter remissions [3,19–21] while others not only demonstrated no impact on prognosis [4,22,23] but even showed a favorable prognosis [24]. Over the years, multiple strategies have been employed to overcome the adverse prognosis
2014 Informa UK Ltd
ISSN 1747-4086
301
Review
Hu, Vikas, Mohty & Savani
associated with FLT3 mutations, with mixed outcomes at best. In this article, we reviewed the effectiveness of hematopoietic stem cell transplantation (HSCT) and tyrosine kinase inhibitors (TKIs), in the treatment of FLT3 AML.
Expert Review of Hematology Downloaded from informahealthcare.com by Nyu Medical Center on 01/09/15 For personal use only.
Efficacy of transplantation for FLT3-ITD AML
When treated with chemotherapy alone, patients with FLT3-ITD AML have a higher rate of relapse compared with their FLT3 wild-type counterparts [3,17,25–27]. While HSCT, during the first complete remission (CR1), has been offered to patients as a therapeutic approach in hopes of overcoming the poor prognostic feature associated with the FLT3-ITD mutation, there have been no randomized clinical trials to demonstrate that HSCT improves overall outcomes. However, multiple retrospective studies have been conducted to evaluate the role of transplant in the treatment of FLT3-ITD+ AML (TABLE 1). A retrospective analysis of 1135 patients showed that FLT3-ITD+ AML was associated with increased relapse even in those who underwent a transplant [28]. Although the study showed decreased relapsed rate in patients with FLT3-ITD+ AML undergoing allograft, there was no difference in OS. The authors of the study, therefore, concluded that the presence of the FLT3 mutation should not affect the decision for transplant. However, those who criticized the interpretation of the study noted that there was no comparison of the outcomes of those who received chemotherapy only versus those who received an allograft [29]. The data showed that the relapse rate for the chemotherapy group was 89% while that of the allograft group was 50% with a relative hazard ratio of 5.9. Additionally, the OS of the chemotherapy group was 8% while that of the allograft group was 43% with a relative hazard ratio of 3.0. Critics of the study also performed an analysis of FLT3-ITD+ AML patients and demonstrated that those who received an autograft had an improved survival over the nontransplanted patients (48 vs 8%, p < 0.05) [29]. However, the original authors of the study contested that the baseline characteristics of the patients who received an autograft were different than those who did not and required cautious interpretation of the data. While outcomes appeared improved in transplant recipients, this discourse demonstrated the need for a prospective, randomized trial comparing outcomes of transplant versus chemotherapy only in patients with FLT3-ITD+ AML while controlling for various baseline patient characteristics which may prove to be difficult to perform in practice. A European group also reported findings in which FLT3-ITD mutation remained a negative prognostic factor even after transplantation [30]. They performed a retrospective analysis with 206 patients with AML who underwent HSCT in CR1. Patients with the FLT3-ITD mutation had a higher relapse incidence at 2 years and a lower disease free survival (DFS) when compared with FLT3 wild-type patients. However, patients with the FLT3-ITD mutation had a better 2-year DFS compared to those who received chemotherapy alone, although the authors acknowledged that selection bias could not be ruled out given that patients 302
who relapsed prior to transplant were excluded from the analysis [30]. Another retrospective study conducted at Vanderbilt University with 79 patients with AML in CR1 who had undergone allogeneic transplantation also confirmed that FLT3-ITD mutation portends a poor prognosis as these patients had a significantly inferior DFS, increased risk of relapse and a trend toward decreased OS [31]. However, there was no comparison of patients with FLT3-ITD+ AML who had undergone only chemotherapy versus those who proceeded to transplant. While the study showed that patients with the FLT3-ITD mutation who underwent transplantation had a low OS, it is unclear if those with FLT3-ITD+ AML who had only undergone consolidation chemotherapy would have had an even worse prognosis. On the other hand, a number of studies demonstrated HSCT to be beneficial for AML patients with FLT3-ITD mutation. A study conducted in Germany was performed on 376 patients who were treated based on the following protocol: patients with a matched sibling donor underwent allogeneic transplantation; those who did not have a matched donor underwent autologous transplantation; and those whose stem cells could not be successfully mobilized, were treated with standard consolidation chemotherapy. The results showed that in patients who underwent autologous or allogeneic transplant, OS was comparable between the FLT3-ITD mutation group and the FLT3 wild-type group, suggesting that transplantation may overcome the negative prognostic factor associated with FLT3-ITD mutation [32]. In contrast, FLT3-ITD+ patients who underwent chemotherapy alone had an inferior probability of survival and a higher probability of relapse when compared to their wild-type counterparts. However, the paper did not elaborate if there were any confounding characteristics of the patients who received chemotherapy alone (i.e., multiple comorbidities, older age, etc.). A retrospective study conducted in Japan also showed similar results. Thirty-four patients with AML were treated with chemotherapy followed by autologous transplantation with similar 5 year DFS and OS in both FLT3-ITD+ and FLT3 wild-type patients [33]. In another study conducted in Italy, 73 patients (22% with FLT3-ITD mutations) with mostly newly diagnosed AML underwent autologous stem cell transplantation following induction and consolidation chemotherapy [34]. OS and DFS were similar between patients with the FLT3 mutation and their wild-type counterparts. The authors of the study did acknowledge that transplanted patients were specifically selected for best response to induction, consolidation and mobilization and that those who relapsed early during consolidation or while waiting for transplant were excluded from analysis. Comparable results were seen in a retrospective analysis with 133 newly diagnosed AML patients under the age of 60 years (23% with FLT3-ITD mutation) at Johns Hopkins in which median survival in patients with FLT3-ITD mutation was similar to that of the entire cohort and that of FLT3 wild-type patients. They theorized that OS was similar in the two groups Expert Rev. Hematol. 7(2), (2014)
informahealthcare.com
1153
206
79
999
34
73
133
37
Gale et al. (2005)
Brunet et al. (2012)
Sengsayadeth et al. (2012)
Bornhauser et al. (2007)
Yoshimoto et al. (2005)
Palmieri et al. (2007)
Dezern et al. (2011)
Singh et al. (2011)
FLT3+ AML patient undergoing consolidation chemotherapy versus auto-sct
FLT3+ versus wild type AML undergoing allo-sct if they had a match, those without a match underwent consolidation chemotherapy
FLT3+ versus wild type AML undergoing auto-sct after induction and consolidation chemotherapy
FLT3+ versus wild type AML undergoing auto-sct and high dose chemotherapy
FLT3+ versus wild type AML undergoing auto-sct, allo-sct, versus consolidation chemotherapy
FLT3+ versus wild type AML in CR1 undergoing allo-sct
FLT3+ AML versus wild type AML undergoing allo-sct in CR1
FLT3-ITD+ AML versus FLT3 wild type AML undergoing auto-sct, allo-sct or chemotherapy
Design
[31]
[32]
[33]
[34]
[35]
[36]
OS between FLT3+ and wild-type were not different in the auto-sct or allo-sct. FLT3+ AML patients who received chemotherapy had lower probability of survival and increased risk of relapse OS and disease free survival were similar between patients with or without FLT3 mutation suggesting that transplant may overcome the poor prognosis associated with FLT3+ AML OS and disease free survival were similar between patients despite FLT3 status suggesting that transplant may overcome the adverse prognosis associated with FLT3+ AML Median OS of FLT3 AML patient was comparable to that of the entire cohort (19.3 vs 15.5 months)
FLT3-ITD patients who underwent an auto-sct in CR1 had improved disease free survival but similar OS when compared to those who received only consolidation therapy
[30]
[28]
Ref.
Patients with FLT3+ AML had inferior DFS (2 year DFS 19 vs 64%, p = 0.0027), increased risk of relapse (1 year: 59 vs 19%, p = 0.01), and trend towards decreased overall survival (p = 0.08) compared to those without the mutation
FLT3+ AML patients had shorter interval from CR to transplantation, higher relapse incidence, lower leukemia-free survival and higher number of chemotherapy courses before reaching CR
FLT3+ AML patients who underwent transplant had an increased relapse compared to wild type counterparts
Summary of results
AML: Acute myeloid leukemia; CR: Complete remission; DFS: Disease-free survival; FLT3: FMS-like tyrosine kinase 3; OS: Overall survival.
Patients (n)
Study (year)
Table 1. Transplantation outcome in FLT3+ AML.
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Management of FLT3 AML: an update
Review
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Review
Hu, Vikas, Mohty & Savani
because of their institution’s policy of aggressively pursuing allogeneic transplantation during CR1 [35]. In an analysis conducted by Schlenk et al., with 872 adult patients with cytogenetically normal AML in which 150 underwent allogeneic transplant for consolidation therapy because of the availability of a matched related donor, benefit of transplant was limited to the subgroup of patients with FLT3-ITD+ or wild-type NPM1+CEBPA without FLT3-ITD [4]. Finally, a retrospective analysis at Harvard University compared autologous stem cell transplantation versus consolidation chemotherapy in 37 adult patients below the age of 60 years with newly diagnosed normal karyotype FLT3-ITD+ AML. Their analysis showed that patients with FLT3-ITD mutation who underwent an autologous stem cell transplant in CR1 had an improved DFS but similar OS when compared to those who received consolidation chemotherapy [36]. While the decision to proceed transplant remains controversial, given the poor prognosis with chemotherapy alone, there has been a trend to offer transplantation despite the studies showing conflicting results [37–39]. For the very least, one study showed that when allogeneic transplantation was performed early during CR1, the survival of young patients with FLT3-ITD+ AML was improved [40]. Current targeted therapy for FLT3 AML
More recently, given the success of TKIs in the treatment of chronic myelogenous leukemia [41,42], much interest has been generated around targeted therapy in the treatment of FLT3-ITD+ AML. TKIs inhibit FLT3, thereby blocking the altered signaling pathway that contributes to the uncontrolled cell proliferation [43]. While many of the TKIs studied are capable of inhibiting both mutant-FLT3 and wild-type FLT3 autophosphorylation, more cytotoxicity was detected in the mutated FLT3 cell lines [44]. Thus, due to their antitumor effects in preclinical trials, TKIs have been investigated in multiple trials to determine their efficacy as a single agent and in combination with other therapies in newly diagnosed, relapsed and refractory populations with FLT3-ITD+ AML (TABLE 2) [45,46]. Currently, preclinical trials show that TKIs combined with chemotherapy in a sequence-specific order exhibit synergistic apoptosis of leukemic cells in vitro [47]. TKI used simultaneously or immediately following chemotherapy produced synergistic cytotoxicity. Antagonism was observed when the TKI was used prior to the chemotherapy. Sorafenib
Sorafenib (BAY 43-9006), an oral multikinase inhibitor [48], approved for use for advanced hepatocellular carcinoma and renal cell carcinoma [49,50], has been the center of multiple clinical trials as targeting therapy against FLT3-ITD+ AML. Sorafenib has been shown to effectively suppress FLT3 autophosphorylation leading to apoptosis of leukemic cells [45,46]. It has also been found to be safe and efficacious in three Phase I trials in patients with refractory or relapsed AML [51–53]. In two 304
of the trials, a decrease in peripheral blasts was noted but the response was transient [51,53]. In the last trial, while no patients achieved complete or partial response, 73% had stable disease and 40% showed a reduction in bone marrow blasts after one cycle. In this trial, sorafenib 400 mg twice daily (b.i.d.) for 21 days was found to be the maximally tolerated dose (MTD) and 55% experienced grade 3 or greater toxicity with the most common being hypokalemia (13%) and fatigue (16%) [52]. In one case report of FLT3-ITD+ AML, molecular remission was induced by sorafenib after allogeneic HSCT [54]. In another case report, the patient was treated with sorafenib for refractory FLT3-ITD+ AML. Although the patient eventually relapsed again and died 22 months after initial diagnosis, FLT3-ITD mutation was no longer detected during sorafenib treatment or at the time of final relapse [55] suggesting that another mechanism other than FLT3 mutation was responsible for the relapse. Sorafenib has also been studied in combination with chemotherapy. In one trial, 10 patients with relapsed AML and 51 patients with untreated AML were treated with both sorafenib and chemotherapy (cytarabine 1.5 g/m2 and idarubicin 12 mg/m2). Seventy five percent achieved a CR including all 15 patients with mutated FLT3-ITD AML although one of the patients experienced CR with incomplete platelet recovery [56]. Only 66% of patients, without the FLT3 mutation, were able to achieve CR. The overall probability of survival at 1 year was 74%. Among the 15 patients with FLT3-ITD AML, 10 relapsed and five remained in CR with a median follow-up of 62 weeks. This trial showed that sorafenib can be safely used in combination with chemotherapy and can achieve a high rate of CR in FLT3-ITD AML. Another trial showed 100% CR in 18 FLT3-ITD+ AML patients who received sorafenib in combination with idarubicin and cytarabine chemotherapy [57]. Median CR duration was 8.8 months and at a median followup of 9 months, 55% had relapsed. DNA sequencing demonstrated no evidence of an acquired FLT3 point mutation at the time of relapse, suggesting that other mechanisms of sorafenib resistance might play a role. A second clinical trial from MD Anderson demonstrated that 5-azacytidine and sorafenib resulted in a response rate of 46% in 37 patients with relapsed or refractory AML [58]. Ninety three percent of patients had a FLT3-ITD mutation; 64% of patients achieved greater than 85% FLT3 inhibition during cycle one of therapy. Median duration of remission was 2.3 months. While the initial high response rate is likely due to a high percentage (64%) of patients achieving adequate FLT3 inhibition, the short time to relapse could be due to the development of drug resistance to sorafenib. In contrast, in a multicenter, randomized, placebo-controlled, double-blind, Phase II trial of 201 elderly (>60 years) patients with AML who received standard 7 + 3 induction chemotherapy with cytarabine and daunorubicin plus two cycles of consolidation therapy with intermediate dose (6 1 g/m2) of cytarabine, sorafenib had no effect on event-free survival (EFS) or OS compared to placebo when given between the cycles and after chemotherapy. However, only 14% of the patients in the Expert Rev. Hematol. 7(2), (2014)
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FLT3, c-KIT, VEGF, NRAS, Raf, PDGF Suppresses FLT3 autophosphorylation and downstream signaling, promotes apoptosis
Phase I/II
Phase I/II/III
Phase IB Phase II
Sorafenib/Bay 43-9006/ Nexavar
Midostaurin/ PKC412
Lestaurtinib/ CEP701
Safe GI effects: 29% Diarrhea: 38% Anemia: 27% Thrombocytopenia: 23%
GI effects: 60–83% Diarrhea: 68% Myleosuppression: 15–18%
Nausea/vomiting, generalized weakness, infection
2.8 100.nM (400 mg, b.i.d.)
10 nM (50–100 mg, b.i.d.)
2–5 nM 40–80 mg b.i.d
Idarubicin and cytarabine: CR + CRP: 75–100% 5-azacytidine: response rate: 46% HSCT: 0–33% CR
Daunorubicin, cytarabine: CR:74% CDDO-Me, HG-7-85-01 and HG-7-86-01, synergistically induces apoptosis in FLT-ITD mutant Salvage chemotherapy: Mitoxantrone Etoposide Cytarabine: CR + CRp: 29%
Peripheral blood: 70% Bone marrow: 25%
CR: 0% Peripheral blood: 0–60% Bone marrow: 0–5%
Side effects
Peripheral blood: 38–73% Bone marrow: 8–66% Resistant: 47%, D835/I386, Y842C mutation [103]
FLT3 IC50(nM) (clinical doses)
Combination with
Clinical response (%)
IC50 refers to the concentration required for the inhibition of FLT3 autophosphorylation. AML: Acute myeloid leukemia; b.i.d.: Twice daily; CR: Complete remission; FLT3-ITD: FMS-like tyrosine kinase 3-internal tandem duplications; GI: Gastrointestinal.
FLT3, TrK A/B/C, VEGFR, STAT5, JAK2, ERK. Inhibits phosphorylation of FLT3, competitively inhibits ATP binding to the Trk kinase domain
FLT3, c-kit, VEGFR-2, PDGFR a and b Suppresses FLT3 autophosphorylation and induces apoptosis in AML
Targets and mechanism
Clinical trial
Inhibitor
Table 2. Published data on FMS-like tyrosine kinase 3 inhibitors.
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[45,46, 48–65,
• Decrease in peripheral blasts but transient responses • Mixed results when combined with transplantation, one study showed synergistic effect with transplant • Combined with cytarbine and idarubicin led to high rates of CR (75–80%)
[74–77]
[66–69]
• High CR rates when combined with chemotherapy in FLT3 AML • A majority of patients (>70%) achieved reduction in bone marrow or peripheral blasts • 36–60% of patients had reductions in bone marrow and peripheral blasts but responses were transient • When combined with chemotherapy, no difference in response between the lestaurtinib group and the control group • The lestaurtinib group was associated with more adverse events, that is, infections • No survival benefit
103,105]
Ref.
Summary
Management of FLT3 AML: an update
Review
305
306
Phase I/II
Phase I/II
Phase I/II
Sunitinib/ SU11248
Tandutinib/ MLN518
KW-2449
FLT3, kit, PDGFR-a, SRC, ABL, aurora kinase. Induces the reduction of phosphorylated histone H3, downregulates FLT3/STAT5, resulting in G1-2/M arrest and apoptosis
FLT3, c-KIT, PDGFR b
FLT3, KIT, VEGFR, PDGFR a and b, RET, CSF-1R Inhibits FLT3-driven phosphorylation and induces apoptosis, inhibits FLT3-induced VEGF production
Targets and mechanism
GI effects, muscular weakness, fatigue
GI effects
30–200 nM 50–700 mg
13 nM 100 mg b.i.d
45% of FLT3-ITD+ patients achieved greater than 50% reduction in peripheral blasts
Cytarabine and daunorubicin produce synergistic antiproliferative effects on FLT3-ITD+ cells in preclinical trial
Mucositis, myelosuppression, bleeding, infection, Diarrhea: 10% Nausea: 10%
50 nM 50–200 mg
RAD001(Rapamycin analog) and cytarabine or daunorubicin in preclinical trials
Peripheral blood:100% in FLT3-mutant, 28% in FTL3-WT
0–75% decreases in PB and BM
Side effects
FLT3 IC50(nM) (clinical doses)
Combination with
Clinical response (%)
IC50 refers to the concentration required for the inhibition of FLT3 autophosphorylation. AML: Acute myeloid leukemia; b.i.d.: Twice daily; CR: Complete remission; FLT3-ITD: FMS-like tyrosine kinase 3-internal tandem duplications; GI: Gastrointestinal.
Clinical trial
Inhibitor
Table 2. Published data on FMS-like tyrosine kinase 3 inhibitors (cont.).
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[81,82]
[78–80]
• Decreased peripheral and bone marrow blasts • Synergistic antiproliferative and pro-apoptic effects on FLT3 blasts when combined with standard induction chemotherapy • Unacceptable side effects and low clinical efficacy has limited further development of this drug for use in clinical trials • Inhibits not only in FLT3-ITD but also FLT3/KDM and WTFLT3 overexpressed leukemia cells • Reductions in peripheral blast counts were transient
[70–73]
Ref.
• 100% of FLT3 mutant developed morphologic or partial responses of short duration • Only 20% of FLT-WT responded to sunitinib
Summary
Review Hu, Vikas, Mohty & Savani
Expert Rev. Hematol. 7(2), (2014)
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Phase I/II
Preclinical
Preclinical
Preclinical
Preclinical
Quizartinib/ AC220
VX322
SKLB1028
BPR1J-097
Linifanib/ ABT-869
AKT, GSK3b, FLT3, VEGF. Inhibits phosphorylation of AKT and GSK3b, induces apoptosis
FLT3, STAT. Suppresses phosphorylation of FLT3 and STAT, induces apoptosis
CDK, FLT3, JAK2. Causes antiproliferation and proapoptotic activity in leukemia cell lines and primary blasts
FLT3 and c-KIT, RTKs with enzyme Ki. Inhibits FLT3-ITD and c-KIT mutations
c-KIT, RET, PDGFR, CSF1R, FLT3
Targets and mechanism
0.55–10 nM in FLT3-ITD In cells, 15 mg alone, 10 mg with cytarabine
Fatigue, febrile neutropenia
• Effective FLT3 inhibition in those with the ITD mutation
• Reduces size of tumor and induces apoptosis in MOLM-13 and MV4-11 murine xenograft models
1–10 nM
Inhibit cells proliferation in AML FLT3-ITD better than FLT-WT and AML FLT3negative in cell lines Cytarabine
• Prolongs survival in a disseminated AML model with wildtype FLT3 and JAK2
17–100 nM
Anti-proliferative effects in a broad range of tumor cell lines and induces G1 cell cycle arrest and apoptosis
Decreased FLT3 phosphorylation seen in 100% (3/3) of FLT3-ITD +, 33% (8/24) of WT/D835 TKD/other unknown mutation. Decreased phosphorylation of ERK 28% of patients
• Prolongs survival of FLT3-ITD mutated mice
• Rapid and relatively durable responses up to 67+ weeks (median 12–14 weeks) • Higher response rate in FLT3-ITD
Summary
