Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1636-1636

Kurzfassung: Patients with AML and hyperleukocytosis (HL) are at increased risk for early death and relapse. HL is associated with a leukostasis syndrome that can potentially lead to acute respiratory distress syndrome or strokes. HL is independently associated with a shorter RFS (Rollig C, Blood 2015). Mediators of inflammation induced by leukemic blasts and endothelial cells contributed to the pathogenesis of leukostasis and could induce chemoresistance (Stucki A, Blood 2001). We hypothesized that a short course of Dexamethasone (DEX) at induction chemotherapy could improve outcome of HL AML pts. From Jan 2004 to Dec 2013, 662 pts (18-75y) were treated in our center by intensive chemo: dauno (60-90 mg/m² d1-3) or idarubicin (8 mg/m² d1-5) with AraC (100-200 mg/m² d1-7); lomustin 200 mg/m² (d1) being added in patients 〉 60y. Hydroxyurea (HU) could be started promptly at diagnosis. Leukapheresis were not performed. Starting from Jan 2010, DEX 10 mg bid d1-3 was systematically added on the chemo backbone of all pts with a WBC 〉 100 x109/L or 50 x109 /L with leukostasis. Supportive care was given according to standard guidelines that did not change across the study period. This retrospective study included 137 patients with WBC 〉 50 x109 /L. The median age was 59.7y (47% ≥60y). Median FU was 4.2 years. 49 pts received DEX and were more likely to have poorer PS, leukostasis syndrome, de novo AML and higher WBC count compared to the 88 pts of the non-DEX group whereas cytogenetics risk and ELN classification were similar. HU was given in 27 pts of the DEX group and in 51 pts of the non-DEX group. AlloSCT was performed in 14 pts of the DEX group and in 19 pts of the non-DEX group. CR rate were 78% (DEX) and 74% (no-DEX), respectively (p=0.357). At d60, 7 pts (14%) had died in the DEX group compared to 17 pts (19%) in the no-DEX group (p=0.457). There were no difference in fungal (p=0.351) or bacterial (p=0.96) infections during induction. There were more grade 3-4 bleeding events (18% vs 7%, p=0.038) and more admissions in ICU (31% vs 15%, p=0.028) in the DEX group. DEX significantly improved DFS (HR 0.41; 95% CI, 0.23-0.74, p=0.003) and OS (HR 0.62; 95% CI, 0.39-0.99, p=0.046) (Figure). In a Fine and Gray model, DEX was associated with a lower risk of relapse (aHR ratio 0.13; 95% CI, 0.05-0.33, p 〈 0.001). In Cox proportional hazards models, DEX was associated with a better DFS (aHR, 0.22; 95% CI, 0.10 to 0.48, p 〈 0.001). An interaction was found between DEX and both the period of treatment (2004-2009 vs2010-2013) and the genetic classification when considering OS meaning that DEX significantly improved OS in patients with intermediate cytogenetic risk and NPM1 mutations especially during the latest period (aHR, 0.07; 95% CI, 0.02 to 0.22, p 〈 0.001). Because of the statistical interaction with NPM1 mutations, we hypothesized that NPM1mut-AML might be particularly sensitive to DEX. Interrogation of transcriptomic data set (Verhaak RG, Haematologica 2009) and data mining algorithm revealed that the NPM1 mutation signature is highly enriched in genes responsive to DEX. OCI-AML3 (NPM1/ DNMT3A mutated) was one of the most sensitive cell line and NPM1mut-AML samples (n=16) were more sensitive to apoptosis induction by DEX compared to non-NPM1mut samples (n=18). Further transcriptomic analyses with TCGA data set (NEJM 2013) revealed more complex molecular interactions between AML subgroups and DEX (DNMT3A, RUNX1 mutations, CBFB-MYH11A were predicted to be responsive). In NSG mice xenografted with OCI-AML3, the combination of DEX+AraC significantly improved mice survival compared to AraC alone (p=0.0001). Lastly, in a PDX-NSG model of chemoresistance (Aroua N, ASH 2015), transcriptomic analyses of in vivo AraC-resistant leukemic cells (after 5 daily doses of 60mg/kg) showed a strong up regulation of genes involved in immune and inflammatory response (including NF-kB network) and a highly significant interaction with DEX-modulated genes suggesting that DEX could downregulate inflammatory pathways responsible for in vivo chemoresistance. DEX improves outcome of AML pts treated by chemotherapy by reducing the risk of relapse. The impact of DEX has been adjusted on several factors to limit biases inherent to non-randomized studies and a strong biological rationale was provided to strengthen the clinical finding. Thus, this finding could be easily translated in routine practice by adding DEX to chemotherapy at least for HL AML pts and/or NPM1 mutations. Figure Figure. Disclosures Récher: Celgene, Sunesis, Amgen, Novartis, Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding. Tavitian:Novartis: Membership on an entity's Board of Directors or advisory committees. Vergez:Novartis: Research Funding. Huguet:Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Sarry:GSK, Novartis: Research Funding.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.1636.1636

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2016

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1718-1718

Kurzfassung: Somatic mutations of isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) genes are found in 7-14% and 8-19% of AML. IDH1R132, IDH2R140 and IDH2R172mutations are most frequent in cytogenetically normal AML (25-30% of cases) and significantly associated with NPM1 mutations (except for IDH2R172). Their prognostic significance depends on mutational context (NPM1 and FLT3-ITD status) and on type of mutation: IDH1R132 has a possible adverse effect, IDH2R140 is associated with a favorable effect while the IDH2R172 effect remains controversial (Green C, Blood 2011; Papaemmanuil E, NEJM 2016). IDH1/2 mutations induce a neomorphic enzyme that overproduces the 2-hydroxyglutarate oncometabolite and thus have emerged as promising therapeutic targets. Indeed, AG-120 (IDH1 inhibitor) and AG-221 (IDH2 inhibitor) have shown encouraging activity in phase I trials including Rel/Ref AML pts though median OS are not yet reported. The prognosis of IDH mutated pts at this phase of the disease is not well described in routine practice outside clinical trials. The primary objective of this study was to describe characteristics and outcome of AML pts with IDH1/2 mutations treated in routine practice by intensive chemotherapy from both diagnosis and Rel/Ref phase of the disease. This study included 1603 pts admitted at the Toulouse University Hospital and/or registered in the Oncomip regional Network from January, 1st, 2000 to December, 31st, 2014. This database included all cases of AML pts treated by intensive chemotherapy since 2000 then, starting from 2007, all consecutive patients whatever their treatment (Bories P, Am J Hematol 2014; Bertoli S, Blood 2013). Molecular analyses were performed at diagnosis or retrospectively from stored samples. Only first relapses after standard intensive chemotherapy were considered for this analysis and refractory disease was defined as failure following one course of induction chemotherapy including or not a second course for patients with more than 5% bone marrow blasts at day 15. Treatment distributions were as follows: 984 pts received intensive chemotherapy, 224 azacitidine and 312 best supportive care. Mutational status of IDH1 and IDH2 was available for 465 pts of whom, 422 received intensive chemotherapy as first line therapy, 21 azacitidine and 20 BSC. The study focalized on pts treated by intensive chemotherapy: 349 IDH1/2wt (82%), 32 IDH1R132 (7.5%), 31 IDH2R140 (7.3%) and 11 IDH2R172 (2.6%). IDH2R140 (59y, IQR, 54-66.5) and IDH2R172 (60y, 42.5-64) pts were older than IDH1R132 (53y, 43.8-59.3) and IDHwt (52y, 39-62) pts. IDH2R172 pts had lower WBC count (2.1 G/l, 1.35-4.6) as compared to IDHwt (18 G/l, 4.3-66.9), IDH1R132 (14.7 G/l, 2.1-47.5) and IDH2R140 (21.5 G/l, 4.1-43). De novo AML was found in 85%, 94%, 74% and 73% of IDHwt, IDH1R132, IDH2R140 and IDH2R172 pts, respectively. Only 3 IDH1R132 and 3 IDH2R140 pts had unfavorable karyotype whereas 2 IDH2R140 pts had CBF-AML. Complete response was achieved in 80%, 91%, 74% and 100% of IDHwt, IDH1R132, IDH2R140 and IDH2R172 pts, respectively. Median overall survival (OS) from diagnosis was 23.6, 20.9, 35.8 and 41.1 months in IDHwt, IDH1R132, IDH2R140 and IDH2R172 pts, respectively. 185 Rel/Ref patients with IDH1/2-defined mutational status received salvage therapy with intensive chemotherapy (68%); azacitidine (18%) or other treatments (14%): 144 IDHwt (36 Ref/108 Rel), 18 IDH1R132 (3 Ref/15 Rel) and 23 IDH2R140/R172 (8 Ref/15 Rel). Complete response was achieved in 62 IDHwt (43%), 9 IDH1R132 (50%) and 12 IDH2R140/R172 (52%) pts, respectively. Median OS and 3-year OS from failure or relapse were: IDHwt: 7.6 months/19%; IDH1R132: 5.9 months/8% and IDH2R140/R172: 11 months/23%. Observational data should be considered complementary to that provided by randomized clinical trials. They provide data collected in a non-selected general population, while participants in clinical trials are generally under very restrictive eligibility criteria. In refractory or relapsed patients who received salvage therapy, substantial differences may be observed according to the subtype of mutations, IDH1R132 having the poorest prognosis. IDH2R172 appears to confer a more favorable outcome (3-year OS from diagnosis: 61%). Disclosures Tavitian: Novartis: Membership on an entity's Board of Directors or advisory committees. Huguet:Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Récher:Celgene, Sunesis, Amgen, Novartis, Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.1718.1718

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2016

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: American Journal of Hematology, Wiley, Vol. 91, No. 2 ( 2016-02), p. 193-198

Kurzfassung: We assessed the influence of obesity on the characteristics and prognosis of acute myeloid leukemia (AML). Indeed, safety of intensive chemotherapy and outcome of obese AML patients in a real‐life setting are poorly described, and chemotherapy dosing remains challenging. We included 619 consecutive genetically‐defined cases of AML treated with intensive chemotherapy between 2004 and 2012. In this cohort, 93 patients (15%) were classified in the obese category according to WHO classification; 59% of them received capped doses of chemotherapy because of a body surface area above 2 m 2 . Obese patients were older and presented more often with cardiovascular comorbidities. Although obese patients had more frequently de novo AML, main characteristics of AML including white blood cell count, karyotype and mutations were well‐balanced between obese and non‐obese patients. After induction chemotherapy, early death and complete remission rates were similar. Overall (OS), event‐free (EFS) and disease‐free (DFS) survival were not significantly different compared to non‐obese patients. However, in the European LeukemiaNet (ELN) favorable subgroup, obese patients had lower median OS, EFS and DFS than non‐obese patients (18.4, 16.8 and 17.2 vs. 43.6, 31.8 and 29.7 months, respectively) and obesity showed a significant impact on OS (OR 2.54; P  = 0.02) in multivariate models. Although we did not find any significant impact of obesity on outcome in the whole series, this study suggests that special efforts for chemotherapy dose optimization are needed in the ELN favorable subgroup since dose capping may be deleterious. Am. J. Hematol. 91:193–198, 2016. © 2015 Wiley Periodicals, Inc.

Materialart: Online-Ressource

ISSN: 0361-8609 , 1096-8652

URL: Issue

URL: Article

DOI: 10.1002/ajh.v91.2

DOI: 10.1002/ajh.24228

Sprache: Englisch

Verlag: Wiley

Publikationsdatum: 2016

ZDB Id: 1492749-4

In: Medicine, Ovid Technologies (Wolters Kluwer Health), Vol. 95, No. 48 ( 2016-12), p. e5356-

Materialart: Online-Ressource

ISSN: 0025-7974

URL: Article

DOI: 10.1097/MD.0000000000005356

Sprache: Englisch

Verlag: Ovid Technologies (Wolters Kluwer Health)

Publikationsdatum: 2016

ZDB Id: 2049818-4

In: Oncotarget, Impact Journals, LLC, Vol. 7, No. 52 ( 2016-12-27), p. 85937-85947

Materialart: Online-Ressource

ISSN: 1949-2553

URL: Issue

URL: Article

DOI: 10.18632/oncotarget.v7i52

DOI: 10.18632/oncotarget.13262

Sprache: Englisch

Verlag: Impact Journals, LLC

Publikationsdatum: 2016

ZDB Id: 2560162-3

In: European Journal of Haematology, Wiley, Vol. 102, No. 2 ( 2019-02), p. 131-142

Kurzfassung: We previously reported the prognostic value of serum ferritin in younger patients with intermediate‐risk acute myeloid leukemia (AML). The aims of this study were to confirm this finding in a larger cohort regardless of age and prognostic subgroups, to explore the expression and functional role of ferritin in AML cells as well as the regulation of serum ferritin levels in AML patients. Patients/Materials/Methods Serum ferritin levels at diagnosis were collected in a cohort of 525 patients treated by intensive chemotherapy. In silico, in vitro , and in vivo analyses were conducted to assess the pattern of expression and functional role of FTH1 and FTL in AML. Results We confirmed the independent prognostic value of serum ferritin. In transcriptomic databases, FTH1 and FTL were overexpressed in AML and leukemic stem cells compared to normal hematopoietic stem cells. The gene signature designed from AML patients overexpressing FTH1 revealed a significant enrichment in genes of the immune and inflammatory response including Nf‐KB pathway, oxidative stress, or iron pathways. This gene signature was enriched in cytarabine‐resistant AML cells in a patient‐derived xenograft model. FTH1 protein was also overexpressed in patient's samples and correlated with the in vitro cytotoxic activity of cytarabine. Lastly, we demonstrated that chemotherapy induced an inflammatory response including a significant increase in serum ferritin levels between day 1 and 8 of induction chemotherapy that was blocked by dexamethasone. Conclusion Ferritin is deregulated in most AML patients likely through inflammation, associated with chemoresistance, and could represent a new therapeutic target.

Materialart: Online-Ressource

ISSN: 0902-4441 , 1600-0609

URL: Issue

URL: Article

DOI: 10.1111/ejh.2019.102.issue-2

DOI: 10.1111/ejh.13183

Sprache: Englisch

Verlag: Wiley

Publikationsdatum: 2019

ZDB Id: 2027114-1

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2802-2802

Kurzfassung: The majority of relapses in acute myeloid leukemia (AML) patients occur in the first or second year following complete remission. In routine, AML patients are followed during five years because few relapses can occur after three or five years. These late or very late relapses remain poorly described, particularly at the molecular level, with only few consistent series in the literature. (Medeiros B et al., Leuk Lymphoma 2007; Verma D et al., Leuk Lymphoma 2010; Watts J et al., Leuk Res 2014). We retrospectively studied all AML relapses occurring after complete remission (CR) obtained with one or two induction cycles between 2000 and 2012 in Toulouse University Hospital, France. Our analyses focused on late relapses (LR, 〉 3 years from CR) and very late relapses (VLR, 〉 5 years from CR) in comparison to early relapses (ER, ≤3 years from CR). Between 2000 and 2012, out of 636 CR patients, 346 had morphological relapses (54.4%). The median time to relapse was 0.9 years (range, 0.1-11.9 years; interquartile range [IQR], 0.5-1.5 years). There were 198 relapses during the first year (57.2%), 82 during the second year (23.7%), 24 during the third year (6.9%) whereas 42 relapses occurred after 3 years (12.1%) and 16 after 5 years (4.6%). Characteristics at diagnosis, i.e., age, AML status, WBC count, karyotype, FLT3-ITD mutation, CEBPA mutation and induction regimen did not differ between ER and LR or VLR. However, NPM1 mutations were more frequent in LR (NPM1m at diagnosis in relapses 〉 3 years: 46% vs. 28% in relapses 〈 3 years, P=.0532), and in VLR (NPM1m at diagnosis in relapses 〉 5 years: 67% vs. 27% % in relapses 〈 5 years, P=.0070). Allogeneic stem cell transplantation (alloSCT) was more frequently performed in the LR group (24% vs. 14%, P=.0369) and in VLR group (31% vs. 14%, P=.0748). Second CR (CR2) rate and median overall survival from relapse date (OS2) were better in LR and VLR than in ER (CR2ER: 26%, CR2LR: 43%, CR2VLR: 50%; P=.0154; OS2ER: 4.6 months, OS2LR: 10.8 months, OS2VLR: 11.6 months; P=.0024). Among the 142 CR1 patients with NPM1m, 67 relapsed (47.2%). In patients with NPM1m, relapses occurred during the first year in 39 (58.2% of NPM1m relapses), during the second year in 14 (20.9%) and during the third year in 2 (3%) whereas 12 relapses occurred after 3 years (17.9%), 8 occurred after 5 years (11.9%) and 3 after 8 years (4.5%). In NPM1-wild type patients, LR and VLR were significantly less frequent ( 〈 3 years: 91.9%; 〉 3 years: 8.1%; 〉 5 years: 2.5%; 〉 8 years: 0.6%; P=.0317, .0037 and .0783 respectively). NPM1m relapses represented one half of LR (48%) and two thirds of VLR (67%). Among them, genotype was NPM1m/FLT3-wild type in most patients (75% in LR and 88% in VLR patients). In LR and VLR, NPM1 mutational status had no impact on CR2 and OS2: CR2LR/NPM1m: 42% vs. CR2LR/NPM1-WT: 38% (P=.8702); CR2VLR/NPM1m: 50%vs. CR2LR/NPM1-WT: 50% (P=1.0000); OS2LR/NPM1m: 7.4 months vs. OS2LR/NPM1-WT: 19.4 months (P=.2019); OS2VLR/NPM1m: 7.8 months vs. OS2VLR/NPM1-WT: 29.8 months (P=.0917). Our data show that LR and VLR are not infrequent in AML patients with NPM1 mutations. Although this finding needs to be validated in updated multicentric cohorts with a very long follow-up, it strongly suggests that AML patients with NPM1 mutations should benefit from a prolonged follow-up beyond 5 years from CR. Table Table. Disclosures No relevant conflicts of interest to declare.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-113109

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2018

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3987-3987

Kurzfassung: Platelet transfusion refractoriness (PTR) is defined by the repeated failure to appropriately increment platelet count after platelet transfusion. PTR represents a real concern in the management of patients (pts) who require iterative platelet transfusions, in particular those undergoing intensive treatment (Stanworth, Br J Haematol 2015). PTR can be secondary to non-immune and immune causes and is associated with adverse events including longer hospital stays, severe hemorrhages and increased risk of early deaths. After induction chemotherapy for acute myeloid leukemia (AML), intensive transfusion support is required during the 4-6 weeks of treatment-induced aplasia. There is few data regarding management and outcome of AML pts with PTR in this setting. This study included all consecutive pts treated by intensive chemotherapy for non-promyelocytic AML in Toulouse University Hospital between January 2001 and December 2014 who developed PTR during the induction phase. Platelet count is measured daily and transfusion of ABO-identical platelets is performed when 〈 10.109/L according to standard guidelines. We pragmatically used a clinical definition of PTR, ie. persistent thrombocytopenia 〈 10.109/L despite at least two successive daily platelet transfusions. Control patients were those treated by intensive chemotherapy without PTR. Intensive chemotherapy consisted in daunorubicin (60-90 mg/m² d1-3) or idarubicin (8 mg/m² d1-5) with cytarabine (100-200 mg/m² d1-7); lomustin being added in pts 〉 60y. We identified 41 cases of PTR among 897 pts in our database (4.8%; 2.9 patients/y). PTR patients were mostly women (78.1% vs 42.4% in non-PTR pts, p 〈 0.0001), with a median age at diagnosis of 57y vs. 59y in non-PTR (table). PTR pts had more often splenomegaly which is a classical factor associated with PTR (22% vs 8.5%, p 〈 0.009). PTR-AML were de novo in 73.2% of cases (only 10 pts had received platelet transfusions prior to initiation of the induction therapy [24.4%]), with cytogenetics and molecular abnormalities not significantly different to non-PTR AML (favorable/intermediate/adverse karyotype: 14.6/61/22% vs 9.1/68/20.4%,; NPM1 mutations: 33.3% vs 33%; FLT3-ITD mutations: 9.7% vs 22.8%). Anti-HLA antibodies were identified in 34/40 PTR pts (82.9%). The median time from chemotherapy initiation to PTR diagnosis was 10.5 days (IQR, 6-16.5). The median duration of thrombocytopenia (from PTR diagnosis to the first platelets count 〉 50.109/L) was 19 days (IQR 15 - 25.5). Management of PTR-pts was as follows: a twice-daily prophylactic transfusion strategy in 30 pts (73.2%) regardless of bleeding events, one or more HLA-matched platelet transfusion in 15 pts (83.3% of 18 patients with matched donors), corticosteroids (n=15, 36.6%), intravenous immunoglobulins (n=14, 34.2%), TPO agonists (n=10, 24.4%) or rituximab (n=1). Median time between PTR diagnosis and first HLA-matched platelet transfusion was 12.5 days (IQR, 6.5-15). There were 7 early deaths in the PTR group (17.1%) compared to 80 (9.3%) in the non-PTR group (p=0.1). Grade 3-4 bleeding events during induction, early death rate (before end of aplasia) by grade 3-4 bleeding and death rate by bleeding regardless of the phase of treatment (induction+consolidation) were significantly higher in the PTR group (respectively 22% vs 4.1%, p 〈 0.0001, 12.2% vs 1.4%, p 〈 0.0006 and 24.4% vs 5.3%, p 〈 0.0001). However, there was no significant difference in 5-year overall survival between both groups (25.9% vs 33.7%, p= 0.35). HLA-matched transfusions have induced an increment in platelet count 〉 10.109/L in 37% of cases.TPO agonists did neither shorten PTR duration (11.5 days with TPO agonists [IQR, 5.5-15] vs. 10.5 days [IQR, 6-16.5] ), nor reduce severe bleeding or early death rate (40% and 20% with TPO agonists vs. 21.9% and 17.1% without). PTR during induction therapy for AML pts significantly increases the risk of early and late deaths by severe bleeding. While TPO agonists did not appear as a relevant strategy for PTR pts, the efficacy of both massive prophylactic and HLA-matched transfusion could have reduced the risk of severe bleeding but remains to be clearly established. Since steroids, immunoglobulins or even rituximab did not prove efficacy in this setting, a better understanding of platelet destruction is needed to design mechanism-based therapeutic strategies for this very high risk condition. Table Table. Disclosures Tavitian: Novartis: Membership on an entity's Board of Directors or advisory committees. Huguet:Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Récher:Celgene, Sunesis, Amgen, Novartis, Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.3987.3987

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2016

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3900-3900

Kurzfassung: NPM1 mutations are frequent in acute myeloid leukemia (AML) and define a distinct entity according to the 2016 WHO classification. NPM1 mutations are generally associated with chemosensitivity and a favorable prognosis. However, outcome may vary according to co-mutational events, and still approximately 40% of patients relapse after achieving complete response. Wild-type NPM1 is mainly located in the nucleolus where it plays a key role in the regulation of ribosome biogenesis, protein synthesis and tumor suppression through TP53 activation. Mutated NPM1 loses its predominant nucleolar location and accumulates in cytoplasm contributing to leukemogenesis (Falini B, Blood 2011). Moreover, this mutational event leads to haploinsufficiency and cytoplasmic retention of wild type NPM1 creating a vulnerability to nucleolar stress. Indeed, complete responses have been observed in NPM1-mutated AML patients with dactinomycin, a nucleolar stress-inducing drug (Falini B, NEJM 2015). Here, we report our experience of off-label dactinomycin in untreated or relapsed/ refractory NPM1-mutated AML. Inclusion criteria for this retrospective study were: age ≥ 18 years-old, AML with NPM1 mutation, relapsed or refractory disease as well as treatment-naive patients unfit for intensive chemotherapy. Patients should also have completed one cycle of dactinomycin 12.5 µg/kg/day for 5 days every 28 days. From September 2015 to February 2019, 26 patients received dactinomycin. Median age was 62.5y, WBC count was 〉 50 giga/L in 8 patients (31%), 13 patients (50%) had FLT3-ITD mutation whereas 10 (38%) and 11 (42%) patients were classified as favorable or intermediate-I according to the ELN-2010 classification. There were 7 (27%) relapses post-allogeneic transplantation. Median number of dactinomycin cycle was 1 (1-8) and 7 patients (27%) received more than 3 cycles. Sorafenib was added in 6 patients with associated FLT3-ITD mutations whereas 2 others patients received ATRA in combination with dactinomycin. Dactinomycin was administered in different situations: front-line treatment in 4 unfit patients (16%); morphologic (n=16, 62%) or molecular relapses (n=4, 16%) following intensive chemotherapy, refractory disease (n=1, 13%) or post remission therapy in second complete response (CR) following salvage chemotherapy (n=1, 13%). Three out of 17 patients (18%) in morphologic relapse or refractory to chemotherapy reached complete remission after the first cycle of dactinomycin. The duration of response was 4 and 6 months in 2 patients whereas the third patient is still in CR 3 years after dactinomycin. One out of 4 patients in molecular relapses achieved a complete molecular remission with dactinomycin. None of the 4 patients unfit for intensive chemotherapy responded to dactinomycin as front-line therapy. The only patient treated in post-CR2 with dactinomycin achieved a complete molecular remission before allogeneic transplantation. Overall, 5 patients (19%) appeared to benefit from dactinomycin treatment. Grade 3-4 adverse events were thrombocytopenia (n=11, 42%), neutropenia (n=11, 42%), GI toxicity (n=6, 23%), mucositis (n=5, 19%), lung infection (n=5, 19%) and skin rash (n=2, 7.6%). Dactinomycin is an inexpensive and easily available drug that may induce significant responses in AML patients with NPM1 mutations with an acceptable safety profile. Prospective and controlled clinical trials are mandatory to clearly define the role of this agent in AML with NPM1 mutations. Disclosures Tavitian: Novartis: Membership on an entity's Board of Directors or advisory committees. Bertoli:Sanofi: Honoraria. Huguet:Incyte Biosciences: Honoraria; Servier: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria. Bories:Abbvie: Consultancy. Recher:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: NPM1 mutations are frequent in acute myeloid leukemia (AML) and define a distinct entity according to the 2016 WHO classification. Wild-type NPM1 is mainly located in the nucleolus where it plays a key role in the regulation of ribosome biogenesis, protein synthesis and tumor suppression through TP53 activation. Mutated NPM1 loses its predominant nucleolar location and accumulates in cytoplasm contributing to leukemogenesis (Falini B, Blood 2011). Moreover, this mutational event leads to haploinsufficiency and cytoplasmic retention of wild type NPM1 creating a vulnerability to nucleolar stress. Indeed, complete responses have been observed in NPM1-mutated AML patients with dactinomycin, a nucleolar stress-inducing drug (Falini B, NEJM 2015).

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-125782

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2019

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Leukemia Research, Elsevier BV, Vol. 75 ( 2018-12), p. 7-10

Materialart: Online-Ressource

ISSN: 0145-2126

URL: Article

DOI: 10.1016/j.leukres.2018.10.015

Sprache: Englisch

Verlag: Elsevier BV

Publikationsdatum: 2018

ZDB Id: 2008028-1