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The Clinical Outcome of Patients With Acute Myeloid Leukemia Expressing FLT3 Internal Tandem Duplication Mutations Could Be Altered by Treatment Regimen
M. Levis, PhD*
B. D. Smith, MD*
E. Garrett, PhD*
R. Zheng, PhD*
B. R. Baldwin, PhD*
M. Malehorn, BS*
L. N’Guyen, BS†
N. Bellal, BS†
J. Allebach, BS*
C. Perot, MD†
C. Civin, MD*‡
N.-C. Gorin, MD†
D. Small, MD, PhD*‡
Departments of *Oncology and ‡Pediatrics, Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
†Department and FAMBA of Hematology, Hopital Saint-Antoine and Université, Paris, France
KEY WORDS: FLT3, internal tandem duplication, acute myeloid leukemia, prognosis, chemotherapy
Several studies have now reported the association of FLT3 internal tandem duplication (FLT3/ITD) mutations and FLT3 D835 point mutations with poor prognosis in acute myeloid leukemia (AML). Chemotherapy regimens used in these studies have varied but in most cases contain combinations of anthracyclines and Ara C. Thus far, no specific treatment regimen has been identified that is capable of impacting on the poor outcomes seen with these mutations. In this study, we analyzed the diagnostic bone marrow samples of patients with AML from 2 separate institutions for the presence of FLT3/ITD and D835 point mutations. When comparing the clinical characteristics and outcomes with respect to FLT3/ITD mutations, clear differences in the rates of complete remission (CR) and overall survival (OS) between the 2 groups of patients were observed. These 2 institutions used different induction and consolidation strategies for their patients, suggesting that some treatment regimens have greater efficacy in this poor-risk subset of patients with AML. Further study of this issue is warranted.
The survival of patients with acute myeloid leukemia (AML) has significantly improved over the past 25 years, but the majority of patients still succumb to the disease. Prognosis is influenced by a number of factors, including white blood cell count on presentation, patient age, and the presence of chromosomal translocations in bone marrow aspirates.1,2 The most recent addition to the list of prognostic factors in AML is the presence of FLT3/ITD mutations and possibly FLT3 D835 point mutations. The FLT3 gene encodes a receptor tyrosine kinase that is normally expressed in hematopoietic stem/progenitor cells but is aberrantly expressed by the leukemic blasts in the majority of AML cases.3-5 FLT3/ITD mutations are localized to the juxtamembrane region of FLT3, whereas D835 point mutations are localized to the kinase domain of the receptor. Both mutations have been shown to constitutively activate the receptor and can lead to perturbations of cellular pathways regulating growth and apoptosis.6-9 The prevalence and prognostic significance of these mutations has been studied in pediatric, adult, and elderly patient populations. A number of independent studies in Japan, Europe, and the United States have established that the prevalence of FLT3/ITD mutations is as high as 34% in AML. An additional 7% of patients with AML express D835 mutations of FLT3. These findings make FLT3 mutations the single most common molecular abnormality known in AML.7,10-20 Patients with AML with FLT3/ITD mutations are consistently characterized as having higher than normal peripheral leucocyte counts and a higher frequency of normal cytogenetics. There is still some controversy as to the exact prognostic significance of these mutations. Although most studies have concluded that FLT3/ITD mutations confer a poor prognosis, considerable variation exists in the reported overall survival (OS) and complete remission (CR) rates for these patients. Possible explanations for these differences include: 1) variations in the patient populations themselves, or in the proportion of patients from whom samples were available for mutation analysis; 2) differences in FLT3/ITD detection methods (different groups have used different techniques); or 3) differences in treatment regimen, although in the studies of FLT3/ITD mutations in adult AML thus far reported, patients received very similar combinations of Ara C and anthracyclines, often with etoposide, as part of institutional or national protocols (UK-MRC, HOVON, CALGB, or JALSG11,13,16,17,20).
We undertook this study to determine the prevalence of FLT3 mutations in 2 similar groups of AML patient samples from 2 different institutions and to compare clinical outcomes with respect to those mutations. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Baltimore, MD) and the Hopital Saint-Antoine (Paris, France) are tertiary care facilities with different therapeutic approaches to patients with AML (non-M3). At Johns Hopkins, patients are given an induction regimen of infusional Ara C with daunomycin daily for 3 days. Consolidation consists of either high-dose Ara C (“HiDAC”) or a repeat cycle of intermediate-dose Ara C with daunomycin. At Saint-Antoine, patients are induced with a double anthracycline regimen of mitoxantrone and daunomycin, then undergo autologous or allogeneic bone marrow transplant (BMT) if CR is achieved.21,22 At both institutions, whenever possible, portions of the diagnostic bone marrow aspirates from patients with AML are stored frozen for research purposes.
The results of this study suggest that although the prevalence of FLT3/ITD mutations is similar between the 2 groups, the clinical outcomes of patients harboring these mutations could be influenced by treatment regimen.
Patients and Methods
Primary diagnostic bone marrow aspirates from patients with AML (excluding FAB M3) were procured as part of an institutional review board-approved protocol. All patients gave informed consent. Cytogenetics were classified as favorable (t8:21 and INV16), unfavorable (5q-, 7q-, or complex), or intermediate (normal, or all others). Mononuclear cells were isolated by Ficoll-Hypaque centrifugation before freezing, as described previously.23
For the time period during which these samples were collected at Johns Hopkins, all patients under age 60 were given an induction regimen of intermediate dose Ara C (667 mg/m2 per day) infused continuously for 3 days, plus 45 mg/m2 per dose daunorubicin daily for 3 days. Patients were given 400 mg/m2 per day etoposide on days 8 through 10. Patients over the age of 60 were treated with “7 + 3,” consisting of 200 mg/m2 per day Ara C infused continuously for 7 days with 45 mg/m2 per dose daunorubicin on days 1 through 3. Consolidation consisted of either high-dose Ara C (“HiDAC”; 2 g/m2 every 12 hours for 6 days) or a repeat 3-day cycle of intermediate-dose Ara C with daunorubicin. At Saint-Antoine, patients were induced with the DON (daunorubicin, oncovin, navantrone) regimen, which consists of vincristine (2 mg/m2) on day 1, daunorubicin 45 mg/m2 per day on days 2 through 4, and mitoxantrone 12 mg/m2 per day on days 2 through 6.21 Patients were then given 2 courses of consolidation. The first was intermediate-dose Ara C (1 g/m2 every 12 hours for 4 days) with amsacrine (120 mg/m2 per day for 3 days) and the second was a course of Ara C (200 mg/m2 per day continuous infusion for 4 days) with etoposide (300 mg/m2 per day for 3 days). Patients achieving remission underwent BMT (allogeneic preferred for patients under the age of 40 with a suitable donor; otherwise, autologous with marrow purged by mafosfamide, a cyclophosphamide derivative) using a preparative regimen of cyclophosphamide (120 mg/kg) and total body irradiation (10 Gy).22
Cytokines (G-CSF or GM-CSF) were not a standard part of the induction regimen at either institution. Complete remission was defined as recovery of cell counts with less than 5% blasts in the bone marrow, as previously described.24
Reverse Transcription-Polymerase Chain Reaction for FLT3/ITD Mutations
Total RNA was isolated from thawed samples using RNeasy columns (Qiagen, Valencia, CA) and reverse-transcribed. Reverse transcription (RT) was performed followed by polymerase chain reaction (PCR) with primers R5 (5’ TGTCGAGCAGTACTCTAAACA-3’) and R6 (5’-ATCCTAGTACCTTCCCAAACTC-3’)(10) using the one-step RT-PCR kit (Invitrogen, Rockville, MD). Products were subjected to electrophoresis on 2.5% agarose gels to identify bands migrating above the expected 365 bp size of the wild-type FLT3 fragment. Dideoxy sequencing was performed on selected samples to confirm FLT3/ITD status. For identification of D835 point mutations, RT-PCR was performed on RNA samples using primers from exon 17 (5’-TTCACAGAGACCTGGCCG-3’ and 5’-TTGCCCCTGACAACATAG-3’). This was followed with EcoRV digestion and electrophoresis on 1.8% agarose gels.7
EOL-1 cells25 were cultured in Roswell Park Medical Institute (RPMI) with 10% fetal bovine serum and penicillin-streptomycin. RNA was prepared and RT-PCR performed as described previously.
Survival curves were calculated by the method of Kaplan-Meier.26 Survival was measured from the date of diagnosis to the date of death (up to February 2001). Statistical comparisons were based on the log rank test.
The bone marrow samples analyzed in this study were obtained from a series of patients presenting with de novo AML at both institutions. All samples for which the clinical outcome was known and for which sufficient cellular material was available for RNA preparation were included. The John Hopkins group consisted of 34 samples collected between April 1997 and August 1999, representing approximately one-third of all adult patients with de novo AML presenting to the institution during that time period. All patients in this group were treated with infusional Ara C and daunomycin (45 mg/m2) on days 1 through 3. The majority of these patients also received etoposide on days 8 through 10 of induction. Six patients underwent BMT (4 allogeneic, 2 autologous) after CR was achieved. The Saint- Antoine group consisted of 35 samples derived from a larger series of 65 patients treated with DON between 1990 and 1999. The clinical outcomes of these patients have been previously reported without respect to their FLT3 mutation status.22 Three of the Saint-Antoine patients were diagnosed before 1989 and were treated with an induction regimen of infusional Ara C and daunomycin on days 1 through 3. Twenty-eight of the 35 Saint-Antoine patients underwent BMT (20 autologous, 8 allogeneic).
RNA was prepared from each of the samples and RT-PCR assays for FLT3/ITD and D835 mutations were performed. Figure1 displays a typical result for the FLT3/ITD assay in which 2 of the 4 samples shown contain the mutation (lanes 3 and 7) demonstrated by the presence of a gel band migrating above the expected 365 bp wild-type PCR product.
Eleven of the 34 (32.4%) Johns Hopkins samples and 12 of 35 (34.3%) of the Saint-Antoine samples expressed FLT3/ITD mutations. This compares with the 13% to 34% prevalence reported in other case studies.14,18
Each of the 2 groups contained 4 specimens with D835 mutations (11.8% and 11.4% for Johns Hopkins and Saint-Antoine, respectively; data not shown). This compares with a 7% prevalence in the 2 published series on this mutation.7,27
Clinical Characteristics and Outcomes
The samples were stratified into 4 groups according to institution and FLT3/ITD status (Johns Hopkins non-ITD, Saint-Antoine non-ITD, Hopkins FLT3/ITD, and Saint-Antoine FLT3/ITD). Age, cytogenetics, peripheral white blood cell (WBC) count at presentation, and achievement of CR are patient characteristics that have been shown to have prognostic importance in AML.1,2 These characteristics are displayed in Table 1. In concordance with the observations of others, the FLT3/ITD-containing samples from both institutions were present in patients with higher-than-average WBC counts and predominantly normal cytogenetics. The patients from Johns Hopkins were somewhat older than the patients from Saint-Antoine, but these differences only reached significance for the non-ITD groups (54 vs. 42 years; P <0.008).
Perhaps the most important prognostic factor in AML is whether a CR is achieved. There was no difference in CR rate between the non-ITD patients from the 2 institutions (74% vs. 83%, P <0.72) despite the slight age difference between these 2 groups (Table 1). In contrast to the non-ITD result, there was a significant difference in CR rate (27% vs. 92%, P <0.003) between the Johns Hopkins FLT3/ITD patients and those from Saint-Antoine. The predominant reason for failure to achieve CR was persistent disease after induction chemotherapy. In each of the 4 groups, a single patient died from infectious complications during the initial induction attempt (i.e., 4 total deaths from infection during the initial induction attempt among all 69 patients), whereas the remainder (15 of 19) had persistent leukemia.
Kaplan-Meier survival estimates for the 4 groups of patients are displayed in Figure 2. In the patients with FLT3/ITD mutations (Fig. 2, left), the Saint-Antoine patients had significantly improved OS (P <0.004) compared with the Johns Hopkins patients. There were no significant differences in age (P <0.18), mean WBC count (P <0.40), or cytogenetic abnormalities (P <0.48) between these 2 groups. By comparison, the non-ITD patients (Fig. 2, right) were much more similar in OS (P <0.11).
The presence of D835 point mutations did not impact on prognosis in this analysis (2 of 4 Johns Hopkins patients and 1 of 4 Saint-Antoine patients were long-term survivors), although the number of samples with this mutation was too small from which to draw any meaningful conclusions.
In this study of bone marrow samples of patients with AML from 2 separate medical institutions, we have confirmed the findings of several other groups regarding FLT3/ITD mutations, namely, that they occur in roughly one-third of AML cases and are more frequently associated with leucocytosis and normal cytogenetics. The presence of these consistent clinical features suggests that the FLT3/ITD patients in this study are a representative selection of patients with AML with this mutation. Additionally, we found a prevalence of D835 mutations of 11.6% in this series. With regard to the prevalence and clinical characteristics of patients with AML with FLT3 mutations, one caveat to consider is that our data (and those of most other groups) is derived from “banked” samples of bone marrow. This could have selected for patients with higher peripheral WBC and bone marrow counts, clinical features which themselves could have prognostic significance and are typical features of FLT3/ITD patients. Hence, estimates based on banked specimens are likely overestimating the true prevalence of these mutations in de novo AML. Thus, conclusions about the clinical outcomes of this population might not be applicable to patients with AML as a whole.
By comparing patients from 2 separate institutions, we have been able to identify a striking difference in clinical outcome between groups of FLT3/ITD patients treated with different regimens. The patients from Johns Hopkins were treated with Ara C-based regimens that resemble those used in other published series examining FLT3/ITD mutations in adult AML. Their OS was poor compared with the patients from the same institution lacking the mutation, which, again, is consistent with the observations of others. In contrast, Saint-Antoine patients were treated with DON followed by Ara C-containing regimens, and, in 28 of 35 cases, with subsequent BMT. The patients who harbored FLT3/ITD mutations in this group achieved significantly improved CR and OS compared with their FLT3/ITD counterparts from Johns Hopkins and experienced a similar outcome to the Saint-Antoine patients lacking the mutation.
At Johns Hopkins, consolidation therapy with BMT is generally reserved for patients with poor-risk cytogenetics. It is possible that the improved OS in the Saint-Antoine patients was, in fact, the result of the use of BMT for consolidation in 28 of 35 patients. It might be appropriate to now characterize patients with FLT3/ITD mutations as being poor risk and to investigate consolidating them with BMT, either allogeneic or autologous. In fact, autologous transplant could be as effective as allogeneic transplant, because 5 of the 7 long-term FLT3/ITD survivors from Saint-Antoine received an autologous mafosfamide-purged BMT. However, transplant would not have been an option for most of the Johns Hopkins patients in this series, because the majority of them did not achieve CR. The remarkably high CR rate of the Saint-Antoine patients raises the possibility that a “nonstandard” chemotherapy regimen such as one based on anthracyclines rather than Ara C could be a better approach to patients with AML with this mutation. Tailoring chemotherapy to a specific molecular abnormality is emerging as an effective treatment strategy in AML. For example, anthracyclines (with all-trans-retinoic acid) are now emphasized in the treatment of acute promyelocytic leukemia, and the use of high-dose Ara C has been associated with improved outcomes in AML cases with core-binding factor abnormalities.28,29 Even with the imminent use of FLT3 tyrosine kinase inhibitors,30-32 a combination chemotherapy regimen specifically designed for patients with AML with FLT3/ITD mutations will likely be necessary to improve the cure rate of patients with this disease.
Although the numbers of patients in this study are not large and the patients come from different institutions, the results are nonetheless important. The use of anthracyclines and the intensity of treatment could affect the clinical outcome of patients with AML expressing FLT3/ITD mutations. A prospective study of larger numbers of patients to confirm these findings might be warranted.
This work was supported by grants from the NCI (CA70970, D.S.C.C.; K23 CA81262-01A1, B.D.S.), Leukemia and Lymphoma Society (D.S.), Children’s Cancer Foundation (D.S.), and an NIH Training Grant (5T32CA09071-201A, M.L.)
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Figure 1. Reverse transcription-polymerase chain reaction (RT-PCR) demonstrating FLT3/ITD mutations in patient samples. RNA was prepared and RT-PCR was performed and analyzed as described in “Methods.” RNA from EOL-1 (human eosinophilic leukemia cell line expressing wild-type FLT3) was used as a control. Lane 1: EOL-1; lanes 3, 5, 7, and 9: patient samples; lanes 2, 4, 6, and 8: the same patient samples but without prior reverse transcription (RT-negative controls).
Table 1. Clinical Characteristics of Patients From Both Institutions, Stratified by FLT3/ITD Status
Johns FLT3/ITD Johns
Total Hopkins St. Antoine Hopkins St. Antoine
Wild-Type FLT3 (N = 69) (N = 23) (N = 23) (N = 11) (N = 12)
Mean age 48.8 54.1 42.2 54.5 46.3
(range) (18-78) (18-68) (18-78) (36-70) (21-63)
Mean whole blood 48.8 23.4 51.5 82.4 64.7
count (range) (0.2-270) (0.2-137.6) (3.4-270) (2.9-246.8) (2.2-190)
Favorable 11 (17%) 6 (27%) 5 (24%) 0 0
Unfavorable 12 (19%) 5 (23%) 6 (29%) 1 (10%) 0
Intermediate 41 (64%) 11 (50%) 10 (48%) 9 (90%) 11 (100%)
M0 2 1 1 0 0
M1 17 5 5 4 3
M2 24 7 11 1 5
M4 16 7 4 2 3
M5 8 2 2 4 0
M6 0 0 0 0 0
M7 1 1 0 0 0
CR 50 (73%) 17 (74%) 19 (83%) 3 (27%) 11 (92%)
FAB, French-American-British AML subtype; CR, complete remission; AML, acute myeloid leukemia.
Figure 2. Kaplan-Meier survival curves (overall survival from time of diagnosis) in non-ITD and FLT3/ITD patients from the 2 different institutions. The y axis depicts the proportion of patients surviving. The numbers at the far right of the Saint-Antoine curves display the number of patients completing 5 years of follow up.
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