Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia

The prognostic significance of FLT3 mutations in acute promyelocytic leukemia (APL) is not firmly established and is of particular interest given the opportunities for targeted therapies using FLT3 inhibitors. We studied 203 patients with PML-RARA–positive APL; 43% of the patients had an FLT3 mutation (65 internal tandem duplications [ITDs], 19 D835/I836, 4 ITD+D835/I836). Both mutations were associated with higher white blood cell (WBC) count at presentation; 75% of the patients with WBC counts of 10 × 109/L or greater had mutant FLT3. FLT3/ITDs were correlated with M3v subtype (P < .001), bcr3 PML breakpoint (P < .001), and expression of reciprocal RARA-PML transcripts (P = .01). Microarray analysis revealed differences in expression profiles among patients with FLT3/ITD, D835/I836, and wild-type FLT3. Patients with mutant FLT3 had a higher rate of induction death (19% vs 9%; P = .04, but no significant difference in relapse risk (28% vs 23%; P = .5) or overall survival (59% vs 67%; P = .2) at 5 years. In in vitro differentiation assays using primary APL blasts (n = 6), the FLT3 inhibitor CEP-701 had a greater effect on cell survival/proliferation in FLT3/ITD+ cells, but this inhibition was reduced in the presence of ATRA. Furthermore, in the presence of CEP-701, ATRA-induced differentiation was reduced in FLT3/ITD+ cells. These data carry implications for the use of FLT3 inhibitors as frontline therapy for APL.

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Clinical Significance of PML/RAR Isoform in Patients of Acute Promyelocytic Leukemia.

Blood ◽

10.1182/blood.v110.11.4218.4218 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4218-4218

Author(s):

Ki-Hyang Kim ◽

Won-Sik Lee ◽

Kyoo-Hyung Lee ◽

Je-Hwan Lee ◽

Seong-Jun Choi ◽

...

Keyword(s):

Acute Promyelocytic Leukemia ◽

Clinical Parameter ◽

Promyelocytic Leukemia ◽

Remission Induction ◽

Induction Treatment ◽

Fusion Transcripts ◽

Induction Group ◽

Significant Difference ◽

Wbc Count ◽

Form Type

Abstract Background: Three types of PML-RARα mRNA fusion transcripts in acute promyelocytic leukemia (APL) could be existed: a short (S)-form type, a long (L)-form type or a variable (V)-form type. Whether 3 types of PML-RARα mRNA fusion transcripts associated with different manifestations and outcomes in individual APL cases are unclear. Recently, some studies reported the controversial results for the relationship between the types of PML-RARα mRNA fusion transcripts and clinical outcomes. But, there was no data about the types of PML-RARα mRNA fusion transcripts especially for the APL patients who were received remission induction therapy with AIDA. Methods: We performed a retrospective analysis for the data of 94 patients with APL, whose isoform data was available. We evaluated the differences of therapeutic outcome of remission induction chemotherapy in terms of response rate, relapse-free survival (RFS), overall survival (OS) and the association of pretreatment clinical parameter characteristics according to the PML-RARα isoforms. Results: The median age of the patients was 41 years (15–85). CR rate following remission induction treatment was 84.9% (AIDA 87.0% vs. non-AIDA 80.0%). Among 94 patients, there were 58 L-form cases (62.1%), 32 S-form cases (34.0%), 4 V-form cases (4.3%). There was no significant difference at any patient’s pretreatment characteristic according to PML-RARα isoform type. CR rate was higher in the group of initial WBC <10,000/ul (93.5% vs. 65.4%, p=0.001). But there was no difference within the isoform L/S subgroup (84.2% vs. 87.2%). And OS and RFS were not different between isoform L/S subgroup (5yr 74.3% vs. 83.1%, 84.2% vs. 85.1%). AIDA induction group was better than non-AIDA induction group regarding OS and RFS (5yr 84.4% vs 55.7%, p=0.026, 90.0% vs 65.7%, p=0.007), but not significant in the multivariate analysis. And also, it was not significantly different in the OS and RFS between isoform L/S subgroup of the AIDA induction group (5yr 80.5% vs. 92.0%, 95.7% vs. 97.0%). Conclusion: This study suggests that high initial WBC count is associated with low CR rate, AIDA induction group has a trend of better OS and RFS, treatment outcomes according to PML-RARα isoform type are not different. Prospective study will be needed to confirm the meaningful significance of PML-RARα isoform type.

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Vitamin E Succinate Induces Remission and Prolongs Survival in a Syngenic Transplant Model of Acute Promyelocytic Leukemia.

Blood ◽

10.1182/blood.v104.11.4953.4953 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4953-4953

Author(s):

Rodrigo S. Abreu e Lima ◽

Priscila S. Scheucher ◽

Bárbara A.A. Santana ◽

Ana Carolina T. Pintão ◽

Ana Sílvia G. Lima ◽

...

Keyword(s):

Vitamin E ◽

Acute Promyelocytic Leukemia ◽

Annexin V ◽

Promyelocytic Leukemia ◽

Rank Test ◽

Histopathological Analysis ◽

Vitamin E Succinate ◽

Significant Difference ◽

Transplant Model

Abstract Vitamin E Succinate (VES) is a semisinthetic analogue of vitamin E with pro-apoptotic activity against several tumor cell lines and it has reported that the association of VES and other antioxidants with first-line chemotherapy may prolong survival of patients with ovarian carcinoma without significant adverse effects. Recently, we have demonstrated in vitro that VES induces apoptosis in primary cells from patients with Acute Promyelocytic Leukemia (APL) as well as in NB4 cells. In order to test in vivo the efficacy of VES treatment, we used a syngenic transplant model of APL. Leukemic blasts from PML/RARα transgenic mice (TM) were IV injected in non transgenic littermates. Recipients were irradiated with 700 cGy 24h prior to transplant. Massive infiltration of bone marrow (BM), spleen and liver was invariable detected by 21st Day. Forty-eight mice were randomly assigned to receive daily intraperitoneal (ip) injections of : VES (50UI/g/d) (n=8), Retinoic Acid (RA) (1.5μg/g/d) (n=7), As2O3 (2.5μg/g/d) (n=8) or the association VES + RA (n=7) and VES + As2O3 (n= 8) at the same doses. Control mice (n=10) were treated with vehicle (DMSO). Treatment was started four days after transplantation and maintained for 21 consecutive days. Survival analysis was based on Kaplan-Meyer estimation and groups were compared by the long-rank test. In any of the five therapeutic arms hematology remission was achieve and survival was significantly longer than in DMSO treated group (P<0.05) (Mean survival time of control: 29.8 days, 95% C.I. = 23.3 – 36.3 days; VES: 66 days, 95%CI = 51.9 – 80.1 days; RA: 60.7 days, 95% CI = 48.1 – 73.2 days; As2O3: 69.7 days, 95% CI = 55.4 –84 days; VES+RA: 49.8 days, 95% CI = 29 – 70.5 days; VES+ As2O3: 70.3 days, 95% CI = 57 – 83.5 days. Treatment toxicity was evaluated by histopathological analysis of heart, lung, brain, liver and kidney paraffin embedded specimens, and no significant organ damage was detected. In order to determine if the antileukemic effect of VES was due to induction of apoptosis, leukemic cells obtained from spleen were treated in vitro with 10, 20, 40μg/mL of VES or DMSO. After 24h cells were harvested and stained with anti-CD117 and anti-annexin V antibody conjugated with phycoerythrin (PE) or fluorescein isothyocyanate (FITC), and the number of CD117 / Annexin V double positive cells (apoptotic) was determined by flow cytometry (FC). The mean percentage of apoptotic cells in samples treated with 40μg/mL of VES (but not with 10 or 20μg/mL) was significantly higher than in controls (83 ± 8% versus 56 ± 4 %, p< 0.05). Differentiation was evaluated morphologically on Leishman stained cytospin preparations after 72h of in vitro treatment of VES at the same doses above. No significant difference in the number of mature granulocytic cells between treated and control samples was observed. In conclusion, our results demonstrate that treatment with VES alone or in combination with RA or As2O3 was well tolerated and extremely effective, and therefore may represent an alternative therapy to relapsed and/or refractory APL cases.

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FLT3 Mutation in Patients with Acute Promyelocytic Leukemia Has No Effect on Therapy Response.

Blood ◽

10.1182/blood.v110.11.4239.4239 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4239-4239

Author(s):

Meng Xing Xue ◽

Hui Ying Qiu ◽

Yu Feng Feng ◽

Jin Lan Pan ◽

Su Ning Chen ◽

...

Keyword(s):

Clinical Outcome ◽

Acute Promyelocytic Leukemia ◽

Prognostic Significance ◽

Therapy Response ◽

Promyelocytic Leukemia ◽

Genetic Changes ◽

Prognostic Effect ◽

Flt3 Mutations ◽

Wbc Count ◽

The Impact

Abstract Fms-Like tyrosine kinase 3 (FLT3) mutations are one of the most frequent genetic changes in acute myeloid leukemia (AML) and are related to poor prognosis. However, in acute promyelocytic leukemia (APL) the prognostic significance of this mutation is not firmly established. We investigated FLT3 internal tandem duplications (FLT3/ITD) or point mutation of the activation loop domain (FLT3/ALM) in initial marrow samples in 160 APL patients, also studied the impact of FLT3 mutations on disease characteristics and clinical outcome. Some of FLT3/ITD+ samples were further examined to determine the ITD allelic ratio(ITD-AR) using Genescan analysis. FLT3/ITD and FLT3/ALM were detected in 31 (19.4%) and 17(10.6%) of the patients, 2(1.25%) showed both ITD and ALM mutations. 19 of 31 FLT3-ITD+ patients were examined to determine ITD-AR, which varied from 0.11 to 1.79, with a median of 0.92. ITD-AR in 8 patients were greater than 1.0. Both mutations were associated with higher white blood cell(WBC) count at presentation(P<0.05); Among patients with WBC counts greater than 10×109/L, FLT3/ITD and FLT3/ALM rates were 49.1%(26/53) and 22.6% (12/53) respectively, were both higher than those of patients with WBC counts lower than 10×109/L (P<0.01). For clinical outcome, the complete remission(CR) of FLT3-ITD+ patients was lower than that of FLT3-ITD− patients(64.5% vs 91.5%, P<0.01), however the CR rates were not significantly different between patients with and without FLT3-LAM(84.6% vs 100%, P>0.05). Six originally FLT3-ITD+ patients were not detectable mutation after remission; so were six patients with originally FLT3-LAM+; however FLT3-LAM in one originally FLT3-LAM+ patient reappeared after relapse. In conclusion, FLT3 mutations (FLT3/ITD or FLT3/ALM) were frequently identified in patients with newly diagnosed APL, and both mutations were associated with higher WBC count at presentation. FLT3/ITD is more frequent than ALM mutation, and predicts a poorer prognosis because of the lower CR rates, while, FLT3/ALM mutation did not show the same unfavorable prognostic effect. In our study, ITD-AR were not found significantly difference between CR and no remission patients (P>0.05)

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Cytochemistry of acute promyelocytic leukemia (M3): leukemic promyelocytes exhibit heterogeneous patterns in cellular differentiation

Blood ◽

10.1182/blood.v66.2.350.350 ◽

1985 ◽

Vol 66 (2) ◽

pp. 350-357 ◽

Cited By ~ 36

Author(s):

M Tomonaga ◽

Y Yoshida ◽

M Tagawa ◽

I Jinnai ◽

K Kuriyama ◽

...

Keyword(s):

Acute Promyelocytic Leukemia ◽

Cellular Differentiation ◽

Remission Rate ◽

Promyelocytic Leukemia ◽

Control Group ◽

Granulocytic Differentiation ◽

Cytochemical Investigation ◽

Significant Difference ◽

Monocytic Lineage

Abstract Cytochemical investigation of leukemic promyelocytes from 25 cases of acute promyelocytic leukemia (M3) disclosed two major cellular differentiation categories: (1) the pure neutrophilic (N) type (16 cases) with strong myeloperoxidase (MPO) and naphthol-ASD chloroacetate esterase (Es-chl), but lacking the monocytic enzyme NaF-sensitive alpha- naphthyl butyrate esterase (Es-b), and (2) the mixed neutrophilic/monocytoid (N/M) type (seven cases) with strong Es-b as well as strong MPO, all cases exhibiting Es-dual (Es-b + Es-chl) positive cells. Two more cases with unusual phenotypes were noted: one with intense lysozyme activity but without Es-b and the other with toluidine blue-methachromasia and negative MPO. Promyelocytes from the control group, consisting of nine cases of t(8;21) M2 AML and ten cases with normal bone marrow, lacked such cytochemical heterogeneity. HL-60, an M3 cell line that can be induced to differentiate toward monocytic lineage in vitro, was almost negative for Es-b in the uninduced condition. Cytogenetically, eight cases of N type and five of N/M type had the t(15;17) abnormality. Thus at least two differentiation patterns were observed in M3 leukemia with fidelity (N type) and infidelity (N/M type) for normal granulocytic differentiation. In this series, there was no statistically significant difference in clinical features (remission rate and survival) between the two types. Our study suggests that the development of M3 leukemia is not exclusively restricted to the neutrophilic pathway, but more heterogeneously related to myelomonocytic differentiation.

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Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity

Blood ◽

10.1182/blood-2006-10-051086 ◽

2007 ◽

Vol 109 (10) ◽

pp. 4450-4460 ◽

Cited By ~ 26

Author(s):

Ronan Quere ◽

Aurelie Baudet ◽

Bruno Cassinat ◽

Gerald Bertrand ◽

Jacques Marti ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Target Genes ◽

Acid Metabolism ◽

Expression Profiles ◽

Promyelocytic Leukemia ◽

Acid Sensitivity ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

AbstractDisease relapse sometimes occurs after acute promyelocytic leukemia (APL) therapy with all-trans retinoic acid (ATRA). Among the diagnostic parameters predicting relapse, heterogeneity in the in vitro differentiation rate of blasts is an independent factor. To identify biologic networks involved in resistance, we conducted pharmacogenomic studies in APL blasts displaying distinct ATRA sensitivities. Although the expression profiles of genes invested in differentiation were similarly modulated in low- and high-sensitive blasts, low-sensitive cells showed higher levels of transcription of ATRA-target genes, transcriptional regulators, chromatin remodelers, and transcription factors. In opposition, only high-sensitive blasts expressed the CYP26A1 gene, encoding the p450 cytochrome which is known to be involved in retinoic acid catabolism. In NB4 cells, ATRA treatment activates a novel signaling pathway, whereby interleukin-8 stimulates the expression of the homeobox transcription factor HOXA10v2, an effective enhancer of CYP26A1 transcription. These data were corroborated in primary APL cells, as maturation levels correlated with CYP26A1 expression. Treatment with a retinoic acid metabolism blocking agent (RAMBA) results in high-nucleoplasmic concentrations of retinoid and growth of NB4-resistant subclones. Hence, for APL blasts associated with poor prognosis, the low CYP26A1 expression may explain high risk of resistance installation, by increased retinoid pressure. Pharmacogenomic profiles of genes involved in retinoid acid metabolism may help to optimize anticancer therapies, including retinoids.

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FLT3 Mutations in a Large Series of Patients with Acute Promyelocytic Leukemia Treated with All-Trans Retinoic Acid and Anthracycline Monochemotherapy.

Blood ◽

10.1182/blood.v108.11.2348.2348 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2348-2348

Author(s):

Pau Montesinos ◽

Marcos Gonzalez ◽

Maria Calasanz ◽

Pascual Bolufer ◽

Dolors Colomer ◽

...

Keyword(s):

Acute Promyelocytic Leukemia ◽

Death Rate ◽

Prognostic Significance ◽

Surface Antigens ◽

Promyelocytic Leukemia ◽

Pcr Analysis ◽

Newly Diagnosed ◽

Wild Type ◽

Significant Difference ◽

Flt3 Mutations

Abstract Background: The prognostic significance of FLT3 internal tandem duplication (ITD) and D835 mutations in acute promyelocytic leukemia (APL) remains unclear. Recent studies have revealed an association between FLT3 mutations and leukocytes > 10x109/L, M3-variant subtype and BCR3 isoform. It has been also suggested that patients with FLT3 mutations have a higher induction death rate and a shorter survival. Objectives: To analyze in patients with newly diagnosed APL treated with an ATRA plus anthracycline-based protocol if the presence of FLT3 ITD and D835 mutations influences the clinical and biological presenting features, and the disease outcome. Material and methods: Between 1997 and 2005, 733 consecutive patients were enrolled in the PETHEMA LPA96 and LPA99 trials. Treatment consisted of Induction therapy with oral ATRA (45 mg/m2/d) and intravenous idarubicin (12 mg/m2/d x 4 days) followed by three courses of consolidation with anthracycline monochemotherapy. In the LPA99 trial, ATRA was added in each cycle of consolidation for intermediate and high risk patients (according to Sanz score). In both trials, maintenance therapy consisted of intermittent ATRA and low dose chemotherapy with methotrexate and 6-mercaptopurine. Using RT-PCR, analysis of the FLT3 ITD and D835 mutations was available in 251 and 191 patients respectively. Results: Overall, 61 patients (24%) had a FLT3 ITD mutation and 20 patients (10%) had a FLT3 D835 mutation. Only one patient had both mutations. FLT3 ITD was associated with BCR3 isoform (78% vs 32%, p < 0.01), leukocytes > 10x109/L (64% vs 17%, p < 0.01), M3v subtype (46% vs 13%, p < 0.01), bone marrow blasts > 70% (95% vs 80%, p < 0.01) and expression of CD2 and CD34 surface antigens (41% vs 14% and 38% vs 9%, respectively, p < 0.01). FLT3 D835 was not associated with leukocytes > 10x109/L (35% vs 25%, p=0.31) or any other biological characteristic. There was a trend towards a higher induction death rate in patients with FLT3 ITD or D835 mutations, when compared to patients with wild-type FLT3 (15% vs 16% vs 6%, respectively, p=0.08). There was no significant difference on relapse-free survival (RFS) and overall survival (OS) at 7 years in patients with FLT3 ITD, when compared to those with FLT3 D835 or wild-type FLT3 (81% vs 100% vs 87% for RFS, p=0.17; and 76% vs 84% vs 81% for OS, p=0.37). Conclusion: In a large cohort of patients with newly diagnosed APL, the incidence of FLT3 ITD and FLT3 D835 mutations was 24% and 10%. This study was only able to demonstrate an association of FLT3 ITD with leukocytes > 10x109/L, M3v subtype, BCR3 isoform, and expression of CD2 and CD34 surface antigens, but this mutation had no independent prognostic value in patients with APL receiving state-of-the-art treatment.

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Cytochemistry of acute promyelocytic leukemia (M3): leukemic promyelocytes exhibit heterogeneous patterns in cellular differentiation

Blood ◽

10.1182/blood.v66.2.350.bloodjournal662350 ◽

1985 ◽

Vol 66 (2) ◽

pp. 350-357

Author(s):

M Tomonaga ◽

Y Yoshida ◽

M Tagawa ◽

I Jinnai ◽

K Kuriyama ◽

...

Keyword(s):

Acute Promyelocytic Leukemia ◽

Cellular Differentiation ◽

Remission Rate ◽

Promyelocytic Leukemia ◽

Control Group ◽

Granulocytic Differentiation ◽

Cytochemical Investigation ◽

Significant Difference ◽

Monocytic Lineage

Cytochemical investigation of leukemic promyelocytes from 25 cases of acute promyelocytic leukemia (M3) disclosed two major cellular differentiation categories: (1) the pure neutrophilic (N) type (16 cases) with strong myeloperoxidase (MPO) and naphthol-ASD chloroacetate esterase (Es-chl), but lacking the monocytic enzyme NaF-sensitive alpha- naphthyl butyrate esterase (Es-b), and (2) the mixed neutrophilic/monocytoid (N/M) type (seven cases) with strong Es-b as well as strong MPO, all cases exhibiting Es-dual (Es-b + Es-chl) positive cells. Two more cases with unusual phenotypes were noted: one with intense lysozyme activity but without Es-b and the other with toluidine blue-methachromasia and negative MPO. Promyelocytes from the control group, consisting of nine cases of t(8;21) M2 AML and ten cases with normal bone marrow, lacked such cytochemical heterogeneity. HL-60, an M3 cell line that can be induced to differentiate toward monocytic lineage in vitro, was almost negative for Es-b in the uninduced condition. Cytogenetically, eight cases of N type and five of N/M type had the t(15;17) abnormality. Thus at least two differentiation patterns were observed in M3 leukemia with fidelity (N type) and infidelity (N/M type) for normal granulocytic differentiation. In this series, there was no statistically significant difference in clinical features (remission rate and survival) between the two types. Our study suggests that the development of M3 leukemia is not exclusively restricted to the neutrophilic pathway, but more heterogeneously related to myelomonocytic differentiation.

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Clinical Outcomes of Acute Promyelocytic Leukemia (APL) Patients According to FLT3 Mutation Status

Blood ◽

10.1182/blood.v116.21.2689.2689 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2689-2689

Author(s):

Harshabad Singh ◽

Lillian Werner ◽

Daniel J DeAngelo ◽

Philip C. Amrein ◽

Martha Wadleigh ◽

...

Keyword(s):

Acute Promyelocytic Leukemia ◽

Clinical Characteristics ◽

Disease Free Survival ◽

Promyelocytic Leukemia ◽

Tyrosine Kinase Receptor ◽

P Value ◽

Mutation Status ◽

Prior Chemotherapy ◽

Flt3 Mutation ◽

Significant Difference

Abstract Abstract 2689 Introduction: Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) characterized by promyelocytes in the blood and bone marrow, coagulopathy, and characteristic translocation between chromosomes 15q22 and 17q21. Internal tandem duplication (ITD) mutations within the FMS-like tyrosine kinase receptor (FLT3) are found in approximately 30% of patients with APL. While cytogenetically normal AML patients with ITD mutations (especially with high ratio of mutant: WT allele) have a poorer prognosis due to high relapse rate, the prognostic value of ITD in APL is debated. We analyzed the clinical outcome of patients with APL to determine the relationship between FLT3 receptor status and prognosis. Materials and Methods: We conducted a retrospective analysis of all adult APL patients < age 60 who were newly diagnosed and tested for FLT3R mutations at Massachusetts General Hospital and Dana-Farber Cancer Institute/Brigham and Women's Hospital between 2002 and 2008. Patient characteristics, complete remission (CR) rates, disease free survival (DFS), and overall survival (OS) were assessed by medical record review under an IRB-approved protocol. CR, DFS and OS were defined according to standard criteria. Kaplan-Meier method was used to estimate median DFS and OS and log-rank p-values were presented. We assessed the associations of clinical characteristics and the type of mutation patients had using Kruskal-Wallis tests. A p-value less than 0.05 was interpreted as statistically significant. Results and Discussion: We identified a total of 26 patients with APL for whom FLT3 mutation status was known. There were 13 patients with wtFLT3, 9 with ITD (1 also had TKD), and the remaining 4 had an isolated TKD mutation. Of the 13 patients with wt FLT3APL, 4 had prior chemotherapy and/or radiation. No patients in the FLT3ITD APL or FLT3TKD APL groups had prior chemotherapy or radiation. As we had only 4 patients had an isolated FLT3TKD mutation, we restricted our analyses to patients who had either wt FLT3 or FLT3ITD+/− TKD. Of the wtFLT3 APL patients, 9/13 were enrolled and treated on CALGB 9710. Of the remaining 4 patients, two were treated according to the PETHEMA regimen, one with a history of breast cancer and significant anthracycline exposure was treated with ATRA and AsO3, and the last patient died before therapy could be initiated. Of the 9 patients with FLT3ITD APL, 5 were treated on CALGB 9710, 2 were treated according to 9710 but off protocol, and 2 with the PETHEMA regimen. Baseline clinical characteristics were similar between the two groups including CR rates [92 (12/13) versus 100% (9/9) for wt and ITD, respectively]. Patients with the ITD had a lower fibrinogen at presentation than those with wt (103 vs. 235 mg/dl, p=.04). While patients with ITD appeared to have a higher WBC, it was not statistically significant (p=.1). However, patients with ITD had an inferior DFS compared to wt (Figure 1) (p=.01) while there was no significant difference in OS between the two groups (p=.39). Of the 5 patients with ITD who relapsed, 3 received AsO3 reinduction and autologous SCT, 1 with CNS recurrence received myeloablative allogeneic SCT, and the fifth died in relapse without treatment. The observation that FLT3ITD APL patients have a reduced DFS raises the possibility that APL therapy may be improved for this group of patients, possibly by incorporating FLT3 inhibitors. Disclosures: DeAngelo: Deminimus: Consultancy. Stone:Novartis: Consultancy.

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ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1603876113 ◽

2016 ◽

Vol 113 (43) ◽

pp. E6669-E6678 ◽

Cited By ~ 35

Author(s):

Mark A. Gregory ◽

Angelo D’Alessandro ◽

Francesca Alvarez-Calderon ◽

Jihye Kim ◽

Travis Nemkov ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Mitochondrial Oxidative Stress ◽

Flt3 Inhibitor ◽

A Genome ◽

Flt3 Inhibitors ◽

Acute Myeloid

Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy. We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.

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In vitro all-trans retinoic acid sensitivity of acute promyelocytic leukemia blasts: a novel indicator of poor patient outcome

Blood ◽

10.1182/blood.v98.9.2862 ◽

2001 ◽

Vol 98 (9) ◽

pp. 2862-2864 ◽

Cited By ~ 30

Author(s):

Bruno Cassinat ◽

Sylvie Chevret ◽

Fabien Zassadowski ◽

Nicole Balitrand ◽

Isabelle Guillemot ◽

...

Keyword(s):

Acute Promyelocytic Leukemia ◽

Promyelocytic Leukemia ◽

Leukemic Cells ◽

Event Free Survival ◽

Free Survival ◽

Acid Sensitivity ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Abstract Acute promyelocytic leukemia (APL) blasts possess a unique sensitivity to the differentiating effects of all-transretinoic acid (ATRA). Multicenter trials confirm that the combination of differentiation and cytotoxic therapy prolongs survival in APL patients. However relapses still occur, and exquisite adaptation of therapy to prognostic factors is essential to aim at a possible cure of the disease. A heterogeneity was previously reported in the differentiation rate of patients' APL blasts, and it was postulated that this may reflect the in vivo heterogeneous outcome. In this study, it is demonstrated that patients of the APL93 trial whose leukemic cells achieved optimal differentiation with ATRA in vitro at diagnosis had a significantly improved event-free survival (P = .01) and lower relapse rate (P = .04). This analysis highlights the importance of the differentiation step in APL therapy and justifies ongoing studies aimed at identifying novel RA-differentiation enhancers.

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