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Commentary
FLT3-ITD in acute promyelocytic leukemia: Clinical distinct profile but still controversial prognosis
Keywords: FLT3 Acute promyelocytic leukemia Prognosis
FLT3 gene, which is located on chromosome 13q12 in humans, encodes a class III tyrosine kinase receptor (RTKs) and plays an important role in the differentiation of hematopoietic stem cells. RTKs are characterized by five immunoglobulin – like regions, such as extra-cellular domain, a juxtamembrane (JM) domain, a transmembrane region, two intracellular tyrosine kinase domains. The interaction with specific ligands leads to receptor dimerization followed by the subsequent phosphorylation of tyrosine residues activating multiple intracellular signaling pathways leading to cell proliferation and activation [1]. Any form of alterations of RTKs, such as overall expression, amplification or somatic mutations, determinate an increased and uncontrolled intracellular signaling definitely causing tumorigenesis [2]. FLT3 mutations including internal tandem duplications (ITD) in the juxtamembrane domain, which frequently involve exon 14 and eventually intron 14 or exon 15, have been reported in 30% of patients affected by acute myeloid leukemia (AML) [3]. An additional mutation have been detected in 5–10% of AML which is a point mutation in the tyrosine kinase II domain (TKD) at Asp835 within exon 20 of the FLT3 gene and resides within the activation loops of the kinase domain of the FLT3 protein [2]. In acute promyelocytic leukemia (APL) the incidence of FLT3-ITD mutation was reported with a wide range (12–38%) [4]. Several prognostic factors have been proposed to negatively influence overall survival (OS), event free survival (EFS) and the risk of relapse in APL patients included older age, high white blood cell count at diagnosis, bcr3 type of transcript, morphologic microgranular variant, additional cytogenetic alterations, and the expression of the surface antigens CD34 and CD56 [5]. The role of FLT3-ITD in APL as a prognostic factor for long-term outcome is not yet clarified and the significance of this genetic alteration remains absolutely controversial. Most of the studies published, showed a strong correlation between FLT3-ITD and specific features at baseline, such as higher WBC count, variant morphologic subtype and short type of transcript. Indeed, not all studies were able to report a clear demonstration of inferior outcome in this subset of patients [4]. Kiyoi et al. identified the mutation in 15 out of 74 (20.3%) newly diagnosed APL patients treated with ATRA plus conventional chemotherapy, with high peripheral blood cell counts, high LDH level and low
fibrinogen concentration, but without differences in complete remission (CR) rate and overall survival (OS) evaluated at 3-years (53% vs 60% of FLT3/ITD−) [6]. In a large series of patients with AML or APL, Kainz et al. evaluated the prognostic significance of FLT3-ITD mutation and found its presence in 38% of APL patients: at 50 months of follow-up no differences were revealed as regards outcome [7]. Noguera et al. investigated the clinico-biological correlations of FLT3-ITD and FLT3-TKD (D835) in 90 patients with APL receiving the AIDA protocol. Thirty-three patients (37%) presented at diagnosis the ITD mutation, while D835 mutation was detected in 7 patients: the presence of ITD, but not that of D835, was strongly associated with clinical adverse prognostic features such as high WBC count, M3 variant morphologic subtype and short isoform transcript. No differences were revealed for remission rate between ITD+ patients and ITD−, but inferior trend was reported in terms of 8-year disease free-survival (DFS) and relapse free-survival [8]. Updated cohort of 147 newly APL treated with the same induction therapy with a considerably longer follow-up of 9 years, was recently reported by the same group: overall, FLT3 mutation was detected in 47 patients of whom 33 (80%) with FLT3-ITD and 14 (20%) with FLT3-TKD. We found a statistical difference in terms of OS (96% in the FLT3-ITD− cohort compared to 39% in the FLT3-ITD+ cohort), relapse free survival (RFS, 90% for FLT3-ITD− compared to 30% for FLT3-ITD+) and cumulative incidence of relapse (CIR, 4% in the FLT3-ITD-negative and 60% in FLT3-ITD+ cohort, respectively) [9]. European APL group evaluated the prognostic implication of FLT3-ITD mutation, FLT3-TKD, N-ras or K-Ras mutations in 119 APL patients, and showed that remission rate, induction death rate and CIR were not influenced by FLT3 and Ras mutation, but a shorter OS in FLT3-ITD+ compared to FLT3− patients was observed [10]. The English group investigated the significance of FLT3-ITD in a large cohort of 203 APL patients, with an incidence of 43%, again associated with higher WBC count at presentation, variant subtype and bcr3 type of transcript, but without evidences that the mutation correlated with significant differences in relapse risk and OS compared to FLT3-ITD− patients, except for induction death rate (19% for FLT3-ITD+ vs 9% in FLT3-ITD− patients) [11]. The Spanish group also analyzed the prognostic significance of FLT3-ITD mutation and size in 129 APL patients enrolled in the Spanish PETHEMA trials: they found that patients with an increased ITD mutant/wild type ratio or longer ITD size displayed shorter 5-year RFS [12]. A German study found that patients with FLT3 mutation/wild type ratio ≥ than 0.5 had better 2-year OS and EFS rates compared to patients with a ratio < than 0.5 [13]. In the PETHEMA/HOVON experience [14], in
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Table 1 FLT3-ITD in APL: outcome and clinical features associated as reported in literature. Reference
FLT3-ITD %
Outcome
Clinical features associated
Kiyoi et al. [6]
No. patients 74
20.3
OS 53% (vs 60% in FLT3− pts)
Noguera et al. [8]
90
37
Inferior trend for RFS and DFS
OS 39% (vs 90% FLT3− pts) RFS 30% (vs 90% FLT3− pts) CIR 4% (vs 60% FLT3− pts) OS 70% (vs 85% FLT3− pts)
-High peripheral blast cell -High LDH value -High WBC count -M3 variant -bcr3 type of transcript -High WBC count -M3 variant -bcr3 type of transcript -High WBC count -M3 variant -bcr3 type of transcript -High WBC count -M3 variant -bcr3 type of transcript -High peripheral blast cell -High LDH value -High WBC count -bcr3 type of transcript -High peripheral blast cell -Low PLTS count -M3 variant -bcr3 type of transcript -High peripheral blast cell -High LDH value -High WBC count -bcr3 type of transcript -fever and coagulopathy -CD2, CD34, HLA-DR, CD11b -High WBC count -bcr3 type of transcript -High WBC count and Hb level -M3 variant -bcr3 type of transcript
Breccia et al. [9]
147
22.4
Callens et al. [10]
119
38
Gale et al. [11]
203
43
No differences in OS High induction death rate (19%)
Chillon et al. [12]
129
21
Lower RFS (23% vs 79% FLT3− pts)
Schnittger et al. [13]
147
32
FLT3 load associated to reduced OS (72.7%) and EFS (62.1%)
Barragan et al. [14]
306
22
Higher induction death rate (16%) Lower RFS 77% (vs 88% FLT3− pts) Lower OS 71% (vs 81% FLT3− pts)
Mathews et al. [15]
94
33
171
20
No differences in OS, EFS and DFS as compared to FLT3− patients Lower OS 62% (vs 82% FLT3− pts)
Lucena-Araujo et al. [20]
OS = overall survival; EFS = event-free survival; RFS = relapse-free survival; CIR = cumulative incidence of relapse; WBC = white blood cell.
univariate analysis FLT3-ITD mutations were associated to higher relapse and lower OS not retained in multivariate analysis, probably due to a shorter median follow-up. Prognostic significance of FLT3-ITD was also tested in 98 APL patients treated with arsenic trioxide (ATO) as single agent. After a median follow-up of 20 months the estimated 3 years OS, EFS and DFS were similar for FLT3+ and FLT3− patients [15]. The introduction of ATO in induction and consolidation therapy seems to overcome the prognostic negative impact of FLT3 mutation seen in patients treated with chemotherapy, as proved by the Australian group and by North American Leukemia Intergroup [16–18]. The impact of mutation was also seen in pediatric population: also in this subset, FLT3ITD was associated with high WBC count, variant subtype and lower remission rate [19]. Recently, an International Consortium on APL identified 35 positive patients out of 171 APL patients screened for FLT3-ITD. Association with typical features was confirmed and after 38 months of follow-up, FLT3-ITD+ patients had lower OS, without differences in DFS, CR rate and CIR [20]. In this number of Leukemia Research, de Souza Melo investigated patterns of WBC count, surface antigen expression, chromosome aberrations, type of transcript and gene expression profile (GEP) in 36 APL patients according to FLT3 status. The authors identified similar correlation with previously reported features and also an association with CD4 and CD2/CD34 expression. In multivariate analysis a WBC count > 20 × 109 /l was predictive for FLT3 positivity. GEP profile identified a specific gene signature with up-regulation of GLT25D2, MS4A3, PON2 and MARCH3 and down-regulation of ZNHIT6, all implicated in hematopoiesis and/or cancer regulation [21]. Another study tested GEP profile in APL patients: Marasca et al. reported on the GEP and FLT3 mutational status in a series of 18 APL patients, clusterized according to morphological and phenotypic features (cluster I represented by M3v with bcr3 and high leukocyte
count and cluster II represented by M3 classic type, bcr1 and leukopenia). FLT3-ITD was found prevalently in cluster I and patients had an increased expression on their blasts of genes regulating blood coagulation (CD97, PTX3, H963) and cell adhesion (AMIGO2, LGALS 1–2) [22]. Two studies that reported different results probably due to hierarchical clustering method used and the small number of patients analyzed with FLT3 positivity (Table 1). All studies published reported a typical association with clinical features at baseline (high WBC count, bcr3 isoform, variant morphological subtype): it is still unknown if higher rates of induction deaths, hemorrhagic complications and higher incidence of retinoic acid syndrome observed in some of these studies were related to higher WBC count or the possible consequence of the associated mutation. Indeed, the role of FLT3-ITD as unfavorable prognostic factor on survival of APL patients remained still controversial and contrasting results have been reported so far. All studies reported that FLT3 did not have an impact on remission rate: therefore the worse outcome described was due to increased rate of relapse, but not all studies were able to demonstrate an inferior outcome in FLT3-ITD+ patients due to relatively small sample sizes analyzed. The identification of a genetic profile associated to FLT3-ITD in APL patients suggests that the presence of this mutation delineate a substantial aggressive subtype of this disease that probably requires a different therapeutic approach. From preliminary results it seems that ATO is able to overcome the inferior outcome of FLT3-ITD+ patients, but larger and prospective studies are needed to confirm its role. Acknowledgements Funding No funding to declare.
Please cite this article in press as: Molica M, Breccia M. FLT3-ITD in acute promyelocytic leukemia: Clinical distinct profile but still controversial prognosis. Leuk Res (2015), http://dx.doi.org/10.1016/j.leukres.2015.01.004
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Authors’ contributions Both MM and MB were involved in researching the literature and writing the paper. MB also critically revised the paper. Conflict of interest statement All authors have no conflict of interest to report. References [1] Matthews W, Jordan CT, Wiegand GW, Pardoll D, Lemischka IR. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell 1991;65:1143–52. [2] Stirewalt DL, Radich JP. The role of FLT3 in hematopoietic malignancies. Nat Rev Cancer 2003;3:650–65. [3] Kottaridis PD, Gale RE, Frew ME, Harrison G, Lanfabeer SE, Belton AA, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 2001;98:1752–9. [4] Beitinjaneh A, Jang S, Roukoz H, Majhail NS. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations in acute promyelocytic leukemia: a systematic review. Leuk Res 2010;34:831–6. [5] Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 2008;111:2505–15. [6] Kiyoi H, Naoe T, Yokota S, Minami S, Kuriyama K, Takeshita A, et al. Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho). Leukemia 1997;11:1447–52. [7] Kainz B, Heintel D, Marculescu R, Schwarzinger I, Sperr W, Le T, et al. Variable prognostic value of FLT3 internal tandem duplications in patients with de novo AML and a normal karyotipe, t(15;17), t(8;21) or inv(16). Hematol J 2002;3:283–9. [8] Noguera NI, Breccia M, Divona M, Diverio D, Costa V, De Santis S, et al. Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol. Leukemia 2002;16:2185–9. [9] Breccia M, Loglisci G, Loglisci MG, Ricci R, Diverio D, Latagliata R, et al. FLT3ITD confers poor prognosis in patients with acute promyelocitic leukemia treated with AIDA protocols: long-term follow-up analysis. Haematologica 2013;98:e161–3. [10] Callens C, Chevret S, Cayuela JM, Cassinat B, Raffoux E, de Botton S, et al. Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group. Leukemia 2005;19:1153–60. [11] Gale RE, Hills R, Pizzey AE, Kottaridis PD, Swirsky D, Gilkes AF, et al. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood 2005;106:3768–76. [12] Chillòn MC, Santamaria C, Garcìa-Sanz R, Balanzategui A, Sarasquete ME, Alcoceba M, et al. Long FLT3 internal tandem duplications and reduced PML-RAR␣ expression at diagnosis characterize a high-risk subgroup of acute promyelocytic leukemia patients. Haematologica 2010;95:745–51. [13] Schnittger S, Bacher U, Haferlach C, Kern W, Alpermann T, Haferlach T. Clinical impact of FLT3 mutation load in acute promyelocytic leukemia with t(15;17)/PML-RARA. Haematologica 2011;96:1799–807.
3
[14] Barragan E, Montesinos P, Camos M, Gonzalez M, Calasanz MJ, Roman-Gomez J, et al. Prognostic value of FLT3 mutations in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy. Haematologica 2011;96:1470–7. [15] Mathews V, Thomas M, Srivastava VM, George B, Srivastava A, Chandy M. Impact of FLT3 mutations and secondary cytogenetic changes on the outcome of patients with newly diagnosed acute promyelocytic leukemia treated with a single agent arsenic trioxide regimen. Haematologica 2007;92:994–5. [16] Iland H, Bradstock K, Seymour J, Hertzberg M, Grigg A, Taylor K, et al. Results of the APML3 trial incorporating all-trans retinoic acid and idarubicin in both induction and consolidation as initial therapy for patients with acute promyelocytic leukemia. Haematologica 2012;97:227–34. [17] Iland H, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, et al. Alltrans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 2012;120:1570–80. [18] Poirè X, Moser BK, Gallagher RE, Laumann K, Bloomfield CD, Powell BL, et al. Arsenic trioxide in front-line therapy of acute promyelocytic leukemia (C9710): prognostic significance of FLT3 mutations and complex karyotype. Leuk Lymphoma 2014;55:1523–32. [19] Kuthy MA, Moser BK, Laumann K, Feusner JH, Gamis A, Gregory J, et al. FLT3 mutation status is a predictor of early death in pediatric acute promyelocytic leukemia: a report from Children’s Oncology Group. Pediatr Blood Cancer 2012;59:662–7. [20] Lucena-Araujo AR, Kim HT, Jacomo RH, Melo RA, Bittencourt R, Pasquini R, et al. Internal tandem duplication of the FLT3 gene confers poor overall survival in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based chemotherapy: an International Consortium on Acute Promyelocytic Leukemia study. Ann Hematol 2014;93:2001–10. [21] De Souza Melo CP, Brant Campos C, Pimenta Dutra A, Aguirre Neto JC, Silva Fenelon AJ, Hallack Neto A, et al. Correlation between FLT3-ITD status and clinical, cellular and molecular profiles in promyelocytic acute leukemia. Leuk Res 2015;39:131–7, http://dx.doi.org/10.1016/j.leukres.2014.11.010. [22] Marasca R, Maffei R, Zucchini P, Castelli I, Saviola A, Martinelli S, et al. Gene expression profiling of acute promyelocytic leukaemia identifies two subtypes mainly associated with FLT3 mutational status. Leukemia 2006;20:103–14.
Matteo Molica Massimo Breccia ∗ Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy ∗ Corresponding
author at: Department of Cellular Biotechnologies and Hematology, Sapienza University, Via Benevento 6, 00161 Rome, Italy. Tel.: +39 06857951; fax: +39 0644241984. E-mail address: [email protected] (M. Breccia) 13 December 2014 Available online xxx
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Commentary
FLT3-ITD in acute promyelocytic leukemia: Clinical distinct profile but still controversial prognosis
Keywords: FLT3 Acute promyelocytic leukemia Prognosis
FLT3 gene, which is located on chromosome 13q12 in humans, encodes a class III tyrosine kinase receptor (RTKs) and plays an important role in the differentiation of hematopoietic stem cells. RTKs are characterized by five immunoglobulin – like regions, such as extra-cellular domain, a juxtamembrane (JM) domain, a transmembrane region, two intracellular tyrosine kinase domains. The interaction with specific ligands leads to receptor dimerization followed by the subsequent phosphorylation of tyrosine residues activating multiple intracellular signaling pathways leading to cell proliferation and activation [1]. Any form of alterations of RTKs, such as overall expression, amplification or somatic mutations, determinate an increased and uncontrolled intracellular signaling definitely causing tumorigenesis [2]. FLT3 mutations including internal tandem duplications (ITD) in the juxtamembrane domain, which frequently involve exon 14 and eventually intron 14 or exon 15, have been reported in 30% of patients affected by acute myeloid leukemia (AML) [3]. An additional mutation have been detected in 5–10% of AML which is a point mutation in the tyrosine kinase II domain (TKD) at Asp835 within exon 20 of the FLT3 gene and resides within the activation loops of the kinase domain of the FLT3 protein [2]. In acute promyelocytic leukemia (APL) the incidence of FLT3-ITD mutation was reported with a wide range (12–38%) [4]. Several prognostic factors have been proposed to negatively influence overall survival (OS), event free survival (EFS) and the risk of relapse in APL patients included older age, high white blood cell count at diagnosis, bcr3 type of transcript, morphologic microgranular variant, additional cytogenetic alterations, and the expression of the surface antigens CD34 and CD56 [5]. The role of FLT3-ITD in APL as a prognostic factor for long-term outcome is not yet clarified and the significance of this genetic alteration remains absolutely controversial. Most of the studies published, showed a strong correlation between FLT3-ITD and specific features at baseline, such as higher WBC count, variant morphologic subtype and short type of transcript. Indeed, not all studies were able to report a clear demonstration of inferior outcome in this subset of patients [4]. Kiyoi et al. identified the mutation in 15 out of 74 (20.3%) newly diagnosed APL patients treated with ATRA plus conventional chemotherapy, with high peripheral blood cell counts, high LDH level and low
fibrinogen concentration, but without differences in complete remission (CR) rate and overall survival (OS) evaluated at 3-years (53% vs 60% of FLT3/ITD−) [6]. In a large series of patients with AML or APL, Kainz et al. evaluated the prognostic significance of FLT3-ITD mutation and found its presence in 38% of APL patients: at 50 months of follow-up no differences were revealed as regards outcome [7]. Noguera et al. investigated the clinico-biological correlations of FLT3-ITD and FLT3-TKD (D835) in 90 patients with APL receiving the AIDA protocol. Thirty-three patients (37%) presented at diagnosis the ITD mutation, while D835 mutation was detected in 7 patients: the presence of ITD, but not that of D835, was strongly associated with clinical adverse prognostic features such as high WBC count, M3 variant morphologic subtype and short isoform transcript. No differences were revealed for remission rate between ITD+ patients and ITD−, but inferior trend was reported in terms of 8-year disease free-survival (DFS) and relapse free-survival [8]. Updated cohort of 147 newly APL treated with the same induction therapy with a considerably longer follow-up of 9 years, was recently reported by the same group: overall, FLT3 mutation was detected in 47 patients of whom 33 (80%) with FLT3-ITD and 14 (20%) with FLT3-TKD. We found a statistical difference in terms of OS (96% in the FLT3-ITD− cohort compared to 39% in the FLT3-ITD+ cohort), relapse free survival (RFS, 90% for FLT3-ITD− compared to 30% for FLT3-ITD+) and cumulative incidence of relapse (CIR, 4% in the FLT3-ITD-negative and 60% in FLT3-ITD+ cohort, respectively) [9]. European APL group evaluated the prognostic implication of FLT3-ITD mutation, FLT3-TKD, N-ras or K-Ras mutations in 119 APL patients, and showed that remission rate, induction death rate and CIR were not influenced by FLT3 and Ras mutation, but a shorter OS in FLT3-ITD+ compared to FLT3− patients was observed [10]. The English group investigated the significance of FLT3-ITD in a large cohort of 203 APL patients, with an incidence of 43%, again associated with higher WBC count at presentation, variant subtype and bcr3 type of transcript, but without evidences that the mutation correlated with significant differences in relapse risk and OS compared to FLT3-ITD− patients, except for induction death rate (19% for FLT3-ITD+ vs 9% in FLT3-ITD− patients) [11]. The Spanish group also analyzed the prognostic significance of FLT3-ITD mutation and size in 129 APL patients enrolled in the Spanish PETHEMA trials: they found that patients with an increased ITD mutant/wild type ratio or longer ITD size displayed shorter 5-year RFS [12]. A German study found that patients with FLT3 mutation/wild type ratio ≥ than 0.5 had better 2-year OS and EFS rates compared to patients with a ratio < than 0.5 [13]. In the PETHEMA/HOVON experience [14], in
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Please cite this article in press as: Molica M, Breccia M. FLT3-ITD in acute promyelocytic leukemia: Clinical distinct profile but still controversial prognosis. Leuk Res (2015), http://dx.doi.org/10.1016/j.leukres.2015.01.004
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Table 1 FLT3-ITD in APL: outcome and clinical features associated as reported in literature. Reference
FLT3-ITD %
Outcome
Clinical features associated
Kiyoi et al. [6]
No. patients 74
20.3
OS 53% (vs 60% in FLT3− pts)
Noguera et al. [8]
90
37
Inferior trend for RFS and DFS
OS 39% (vs 90% FLT3− pts) RFS 30% (vs 90% FLT3− pts) CIR 4% (vs 60% FLT3− pts) OS 70% (vs 85% FLT3− pts)
-High peripheral blast cell -High LDH value -High WBC count -M3 variant -bcr3 type of transcript -High WBC count -M3 variant -bcr3 type of transcript -High WBC count -M3 variant -bcr3 type of transcript -High WBC count -M3 variant -bcr3 type of transcript -High peripheral blast cell -High LDH value -High WBC count -bcr3 type of transcript -High peripheral blast cell -Low PLTS count -M3 variant -bcr3 type of transcript -High peripheral blast cell -High LDH value -High WBC count -bcr3 type of transcript -fever and coagulopathy -CD2, CD34, HLA-DR, CD11b -High WBC count -bcr3 type of transcript -High WBC count and Hb level -M3 variant -bcr3 type of transcript
Breccia et al. [9]
147
22.4
Callens et al. [10]
119
38
Gale et al. [11]
203
43
No differences in OS High induction death rate (19%)
Chillon et al. [12]
129
21
Lower RFS (23% vs 79% FLT3− pts)
Schnittger et al. [13]
147
32
FLT3 load associated to reduced OS (72.7%) and EFS (62.1%)
Barragan et al. [14]
306
22
Higher induction death rate (16%) Lower RFS 77% (vs 88% FLT3− pts) Lower OS 71% (vs 81% FLT3− pts)
Mathews et al. [15]
94
33
171
20
No differences in OS, EFS and DFS as compared to FLT3− patients Lower OS 62% (vs 82% FLT3− pts)
Lucena-Araujo et al. [20]
OS = overall survival; EFS = event-free survival; RFS = relapse-free survival; CIR = cumulative incidence of relapse; WBC = white blood cell.
univariate analysis FLT3-ITD mutations were associated to higher relapse and lower OS not retained in multivariate analysis, probably due to a shorter median follow-up. Prognostic significance of FLT3-ITD was also tested in 98 APL patients treated with arsenic trioxide (ATO) as single agent. After a median follow-up of 20 months the estimated 3 years OS, EFS and DFS were similar for FLT3+ and FLT3− patients [15]. The introduction of ATO in induction and consolidation therapy seems to overcome the prognostic negative impact of FLT3 mutation seen in patients treated with chemotherapy, as proved by the Australian group and by North American Leukemia Intergroup [16–18]. The impact of mutation was also seen in pediatric population: also in this subset, FLT3ITD was associated with high WBC count, variant subtype and lower remission rate [19]. Recently, an International Consortium on APL identified 35 positive patients out of 171 APL patients screened for FLT3-ITD. Association with typical features was confirmed and after 38 months of follow-up, FLT3-ITD+ patients had lower OS, without differences in DFS, CR rate and CIR [20]. In this number of Leukemia Research, de Souza Melo investigated patterns of WBC count, surface antigen expression, chromosome aberrations, type of transcript and gene expression profile (GEP) in 36 APL patients according to FLT3 status. The authors identified similar correlation with previously reported features and also an association with CD4 and CD2/CD34 expression. In multivariate analysis a WBC count > 20 × 109 /l was predictive for FLT3 positivity. GEP profile identified a specific gene signature with up-regulation of GLT25D2, MS4A3, PON2 and MARCH3 and down-regulation of ZNHIT6, all implicated in hematopoiesis and/or cancer regulation [21]. Another study tested GEP profile in APL patients: Marasca et al. reported on the GEP and FLT3 mutational status in a series of 18 APL patients, clusterized according to morphological and phenotypic features (cluster I represented by M3v with bcr3 and high leukocyte
count and cluster II represented by M3 classic type, bcr1 and leukopenia). FLT3-ITD was found prevalently in cluster I and patients had an increased expression on their blasts of genes regulating blood coagulation (CD97, PTX3, H963) and cell adhesion (AMIGO2, LGALS 1–2) [22]. Two studies that reported different results probably due to hierarchical clustering method used and the small number of patients analyzed with FLT3 positivity (Table 1). All studies published reported a typical association with clinical features at baseline (high WBC count, bcr3 isoform, variant morphological subtype): it is still unknown if higher rates of induction deaths, hemorrhagic complications and higher incidence of retinoic acid syndrome observed in some of these studies were related to higher WBC count or the possible consequence of the associated mutation. Indeed, the role of FLT3-ITD as unfavorable prognostic factor on survival of APL patients remained still controversial and contrasting results have been reported so far. All studies reported that FLT3 did not have an impact on remission rate: therefore the worse outcome described was due to increased rate of relapse, but not all studies were able to demonstrate an inferior outcome in FLT3-ITD+ patients due to relatively small sample sizes analyzed. The identification of a genetic profile associated to FLT3-ITD in APL patients suggests that the presence of this mutation delineate a substantial aggressive subtype of this disease that probably requires a different therapeutic approach. From preliminary results it seems that ATO is able to overcome the inferior outcome of FLT3-ITD+ patients, but larger and prospective studies are needed to confirm its role. Acknowledgements Funding No funding to declare.
Please cite this article in press as: Molica M, Breccia M. FLT3-ITD in acute promyelocytic leukemia: Clinical distinct profile but still controversial prognosis. Leuk Res (2015), http://dx.doi.org/10.1016/j.leukres.2015.01.004
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ARTICLE IN PRESS Commentary / Leukemia Research xxx (2015) xxx–xxx
Authors’ contributions Both MM and MB were involved in researching the literature and writing the paper. MB also critically revised the paper. Conflict of interest statement All authors have no conflict of interest to report. References [1] Matthews W, Jordan CT, Wiegand GW, Pardoll D, Lemischka IR. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell 1991;65:1143–52. [2] Stirewalt DL, Radich JP. The role of FLT3 in hematopoietic malignancies. Nat Rev Cancer 2003;3:650–65. [3] Kottaridis PD, Gale RE, Frew ME, Harrison G, Lanfabeer SE, Belton AA, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 2001;98:1752–9. [4] Beitinjaneh A, Jang S, Roukoz H, Majhail NS. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations in acute promyelocytic leukemia: a systematic review. Leuk Res 2010;34:831–6. [5] Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 2008;111:2505–15. [6] Kiyoi H, Naoe T, Yokota S, Minami S, Kuriyama K, Takeshita A, et al. Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho). Leukemia 1997;11:1447–52. [7] Kainz B, Heintel D, Marculescu R, Schwarzinger I, Sperr W, Le T, et al. Variable prognostic value of FLT3 internal tandem duplications in patients with de novo AML and a normal karyotipe, t(15;17), t(8;21) or inv(16). Hematol J 2002;3:283–9. [8] Noguera NI, Breccia M, Divona M, Diverio D, Costa V, De Santis S, et al. Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol. Leukemia 2002;16:2185–9. [9] Breccia M, Loglisci G, Loglisci MG, Ricci R, Diverio D, Latagliata R, et al. FLT3ITD confers poor prognosis in patients with acute promyelocitic leukemia treated with AIDA protocols: long-term follow-up analysis. Haematologica 2013;98:e161–3. [10] Callens C, Chevret S, Cayuela JM, Cassinat B, Raffoux E, de Botton S, et al. Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group. Leukemia 2005;19:1153–60. [11] Gale RE, Hills R, Pizzey AE, Kottaridis PD, Swirsky D, Gilkes AF, et al. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood 2005;106:3768–76. [12] Chillòn MC, Santamaria C, Garcìa-Sanz R, Balanzategui A, Sarasquete ME, Alcoceba M, et al. Long FLT3 internal tandem duplications and reduced PML-RAR␣ expression at diagnosis characterize a high-risk subgroup of acute promyelocytic leukemia patients. Haematologica 2010;95:745–51. [13] Schnittger S, Bacher U, Haferlach C, Kern W, Alpermann T, Haferlach T. Clinical impact of FLT3 mutation load in acute promyelocytic leukemia with t(15;17)/PML-RARA. Haematologica 2011;96:1799–807.
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[14] Barragan E, Montesinos P, Camos M, Gonzalez M, Calasanz MJ, Roman-Gomez J, et al. Prognostic value of FLT3 mutations in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy. Haematologica 2011;96:1470–7. [15] Mathews V, Thomas M, Srivastava VM, George B, Srivastava A, Chandy M. Impact of FLT3 mutations and secondary cytogenetic changes on the outcome of patients with newly diagnosed acute promyelocytic leukemia treated with a single agent arsenic trioxide regimen. Haematologica 2007;92:994–5. [16] Iland H, Bradstock K, Seymour J, Hertzberg M, Grigg A, Taylor K, et al. Results of the APML3 trial incorporating all-trans retinoic acid and idarubicin in both induction and consolidation as initial therapy for patients with acute promyelocytic leukemia. Haematologica 2012;97:227–34. [17] Iland H, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, et al. Alltrans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 2012;120:1570–80. [18] Poirè X, Moser BK, Gallagher RE, Laumann K, Bloomfield CD, Powell BL, et al. Arsenic trioxide in front-line therapy of acute promyelocytic leukemia (C9710): prognostic significance of FLT3 mutations and complex karyotype. Leuk Lymphoma 2014;55:1523–32. [19] Kuthy MA, Moser BK, Laumann K, Feusner JH, Gamis A, Gregory J, et al. FLT3 mutation status is a predictor of early death in pediatric acute promyelocytic leukemia: a report from Children’s Oncology Group. Pediatr Blood Cancer 2012;59:662–7. [20] Lucena-Araujo AR, Kim HT, Jacomo RH, Melo RA, Bittencourt R, Pasquini R, et al. Internal tandem duplication of the FLT3 gene confers poor overall survival in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based chemotherapy: an International Consortium on Acute Promyelocytic Leukemia study. Ann Hematol 2014;93:2001–10. [21] De Souza Melo CP, Brant Campos C, Pimenta Dutra A, Aguirre Neto JC, Silva Fenelon AJ, Hallack Neto A, et al. Correlation between FLT3-ITD status and clinical, cellular and molecular profiles in promyelocytic acute leukemia. Leuk Res 2015;39:131–7, http://dx.doi.org/10.1016/j.leukres.2014.11.010. [22] Marasca R, Maffei R, Zucchini P, Castelli I, Saviola A, Martinelli S, et al. Gene expression profiling of acute promyelocytic leukaemia identifies two subtypes mainly associated with FLT3 mutational status. Leukemia 2006;20:103–14.
Matteo Molica Massimo Breccia ∗ Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy ∗ Corresponding
author at: Department of Cellular Biotechnologies and Hematology, Sapienza University, Via Benevento 6, 00161 Rome, Italy. Tel.: +39 06857951; fax: +39 0644241984. E-mail address: [email protected] (M. Breccia) 13 December 2014 Available online xxx
Please cite this article in press as: Molica M, Breccia M. FLT3-ITD in acute promyelocytic leukemia: Clinical distinct profile but still controversial prognosis. Leuk Res (2015), http://dx.doi.org/10.1016/j.leukres.2015.01.004
