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Adult T-cell acute lymphoblastic leukemia has a poor outcome after relapse. Because the subtype of early T-cell precursor displays characteristics close of those of acute myeloid leukemia, such as epigenetic dysregulation, hypomethylating agents might prove of interest. We describe the case of a patient relapsing 3 months only after allogeneic stem cell transplantation who achieved complete remission on azacitidine, and is still on therapy 9 years later. We discuss the biological background of this very long-term response, underlining the immunological effects of hypomethylating agents, and the perspectives opened by combination of hypomethylating agents with other drugs such as venetoclax. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) with myelodysplasia‐related characteristics is a heterogeneous subset of AML that has been challenged throughout the history of myeloid malignancies classifications, considered to have similar outcomes as intermediate‐ or adverse‐risk AML depending on the subgroup. However, little is known about the fate of these patients in refractory or relapsed situation (R/R) after first line therapy. Methods: A large series of R/R AML patients, recorded in the French DATAML registry, have received either intensive chemotherapy (ICT), azacitidine (AZA) as single agent, or best supportive care (BSC). A cohort of 183 patients (median age 63‐year‐old) with what was called at the time AML‐MRC has been explored, and data are reported here. Results: Patient status was refractory for 93, while 90 had relapsed. Respectively, 88, 34, and 61 were included in the three treatment arms. The median OS of the whole cohort was 4.2 months (95%CI: 3.1–5.6) with a mean 1‐year overall survival of 24% ± 3.2%. There was no significant survival difference between refractory and relapsed patients. The BSC group had overall a significantly worse outcome (p = 0.0001), and this remained true in both refractory (p = 0.01) and relapsed (p = 0.002) patients. Similar survivals were observed in both groups comparing ICT and AZA. Conclusions: These data, reporting about an ill‐explored population, indicate the poor prognosis of this condition where both ICT and AZA can be proposed. The latter, which was demonstrated here to be a feasible option, should be added to new targeted therapies. [ABSTRACT FROM AUTHOR]

Previous studies of MS have reported a CR rate of 45%-70% after IC and median OS of 12.8-15.9 months.[[11], [13]] Our multi-variate Cox model showed that an age >65 years, a BM blast rate >=20% and patients with refractory or relapsing disease were independently associated with mortality. Myeloid sarcoma (MS) accounts for 3%-8% acute myeloid leukaemia (AML) cases and is characterized by an extramedullary proliferation of myeloid blast cells forming a solid tumour,[1] with or without bone marrow (BM) involvement.[[2]] A history of other myeloid neoplasms can precede MS occurrence.[4] MS literature is scarce with mostly heterogeneous cohorts mixing primary MS with extramedullary AML relapses. Patients with extramedullary AML relapses and with no MS at their first AML diagnosis were excluded, but patients with a history of MDS/MPN were eligible. The median OS was not reached for patients with a bone marrow (BM) blast rate <20% versus 24 months for patients with a BM blast rate >=20%. [Extracted from the article]

17341661 9 Galtier J, Alric C, Bérard E, Leguay T, Tavitian S, Bidet A. Intermediate-dose cytarabine or standard-dose cytarabine plus single-dose anthracycline as post-remission therapy in older patients with acute myeloid leukemia: impact on health care resource consumption and outcomes. Dear Editor, The gold standard post-remission treatment in younger patients with acute myeloid leukemia (AML) in first complete remission after induction chemotherapy was based until recently on high-dose cytarabine (HDAC) delivered every 12 h on Days 1, 3, and 5 (HDAC-135) [[1]]. According to AML incidence in France and taking into account patient age distribution and the fact that 50% of patients have chemotherapy and 70% of them undergo post-remission treatment, 1200 AML patients made up of 317 younger and 883 older subjects respectively receive post-remission regimens annually [[12]]. We have completed the cost comparison of two post-remission treatments for younger (HDAC-123) and older (SDAC/a) AML patients versus standards of care and considering inpatient stay costs using the FNHI perspective. [Extracted from the article]

Background: Recently, the combination of venetoclax plus a hypomethylating agent (HMA; azacitidine ordecitabine) or low‐dose cytarabine (LDAC) showed promise in Phase III trials in previously untreated AML. In France at the time of this study, venetoclax was not yet approved for AML and there were therefore no formal usage recommendations. Here we report the first study in a French cohort that assessed venetoclax in combination with existing treatments for AML under real‐life conditions. Method: This retrospective, real‐life study collected data on venetoclax use and management in a French cohort with acute myeloid leukemia (AML) ineligible for intensive chemotherapy. Result: Of 118 patients, 81 were in second line/beyond (71.6% also hypomethylating agent [HMA]; 23.5% lowdose cytarabine [LDAC]) and 37 in first line. For venetoclax initiation, 57.3% underwent ramp up and 74.6% were hospitalized. Median venetoclax duration was 2.5 months (range 0.03‐16.2). With all treatment lines and regimens, most common grade 3/4 adverse events were hematologic (overall 96.4% of patients) and infections (57.1%). Dosage adjustments for drug interactions and safety varied between centers. In second‐line/beyond, median progression‐free survival was 4.0 months (95% confidence interval [CI] 2.7‐12.8) with venetoclax‐HMA and 3.4 months (1.3‐8.9) with venetoclax‐LDAC; overall response rate was 51.9% and 41.2%, respectively. Thus, we showed that venetoclax‐based treatment yields promising findings in patients with AML, but to address treatment complexity, practice harmonization is needed. [ABSTRACT FROM AUTHOR]

Classifications of acute myeloid leukemia (AML) patients rely on morphologic, cytogenetic, and molecular features. Here we have established a novel flow cytometry-based immunophenotypic stratification showing that AML blasts are blocked at specific stages of differentiation where features of normal myelopoiesis are preserved. Six stages of leukemia differentiation-arrest categories based on CD34, CD117, CD13, CD33, MPO, and HLA-DR expression were identified in two independent cohorts of 2087 and 1209 AML patients. Hematopoietic stem cell/multipotent progenitor-like AMLs display low proliferation rate, inv(3) or RUNX1 mutations, and high leukemic stem cell frequency as well as poor outcome, whereas granulocyte–monocyte progenitor-like AMLs have CEBPA mutations, RUNX1-RUNX1T1 or CBFB-MYH11 translocations, lower leukemic stem cell frequency, higher chemosensitivity, and better outcome. NPM1 mutations correlate with most mature stages of leukemia arrest together with TET2 or IDH mutations in granulocyte progenitors-like AML or with DNMT3A mutations in monocyte progenitors-like AML. Overall, we demonstrate that AML is arrested at specific stages of myeloid differentiation (SLA classification) that significantly correlate with AML genetic lesions, clinical presentation, stem cell properties, chemosensitivity, response to therapy, and outcome. [ABSTRACT FROM AUTHOR]

We analyzed 526 consecutive acute myeloid leukemia patients refractory to or relapsing after chemotherapy. 270 patients received intensive salvage chemotherapy (IC), 97 azacitidine (AZA) and 159 best supportive care (BSC). Complete response was obtained in 37/19/0% (p =.0008). Allogeneic stem-cell transplantation (alloSCT) was performed in 39.3/10.3/0%. Median overall survival (OS) and 5-year OS were 8.2/9.6/2.2 months and 16/6/2% (p <.0001). Predictive factors of worse OS were post-myelodysplastic/chronic myelomonocytic leukemia, bone marrow blasts ≥20%, adverse cytogenetics, AZA cycle ≥2 and no alloSCT at R/R for AZA and age, performance status, white blood cell count and myelodysplasia-related changes for IC. The impact of treatment was time-dependent: adjusted hazard ratio for OS was in favor of AZA up to 1 month, was not different between 1 and 7 months, then was in favor of IC after 7 months. While AZA represents a therapeutic option for the oldest patients, it does not lead to long-term survivors. [ABSTRACT FROM AUTHOR]

Midostaurin combined with intensive chemotherapy has improved the outcome of AML patients with I FTL3 i mutations (~60% of patients in our series) including ELN 2017 adverse risk patients [[10]]. A total of 616 mutations were identified with an average of 4 mutations per patient (0-10 mutations/patient). Diagnostic samples for NGS analyses were available for 154 patients (96.3%), 59 patients who received dexamethasone, and 95 patients who did not. In patients with I FLT3 i mutations, 12 had co-mutations in I IDH1 i , and 12 patients had co-mutations in I IDH2 i . [Extracted from the article]

Considering the whole post-remission program, the median red blood cell transfusion per patient was 8.0 units (range, 0.0-18.0) in the IDAC arm and 4.0 (range, 0.0-24.0) in the SDAC-IDA arm ( I p i < 0.0001). Considering the whole post-remission program, the median platelet transfusion per patient was 6.0 units (range, 0.0-19.0) in the IDAC arm and 3.0 (range, 0.0-23.0) in the SDAC-IDA arm ( I p i < 0.0001). Patients receiving the SDAC-IDA regimen spent on average 20 days less in hospital over the whole period of post-remission treatment. [Extracted from the article]

Acute myeloid leukemia (AML) intensive chemotherapy combined with broad-spectrum antibiotics, leads to gut microbiota dysbiosis promoting pathological conditions and an increased incidence of complications. Here we report findings from a phase II single-arm, multicenter study evaluating autologous fecal microbiota transfer (AFMT) in 25 AML patients treated with intensive chemotherapy and antibiotics (ClinicalTrials.gov number: NCT02928523). The co-primary outcomes of the study are to evaluate the efficacy of AFMT in dysbiosis correction and multidrug-resistant bacteria eradication. The main secondary outcomes are to define a dysbiosis biosignature, to evaluate the effect of dysbiosis correction on patient clinical status, to assess the short and mid-term safety of AFMT in this immunocompromised population, and to evaluate the feasibility of the AFMT procedure and acceptability by the patient. Intensive induction chemotherapy induces a dramatic decrease of α-diversity indices, and a microbial dysbiosis with a significant shift of the microbial communities and domination of pro-inflammatory families. After AFMT treatment, α-diversity indices return to their initial mean levels and the similarity index shows the restoration of microbial communities. The trial meets pre-specified endpoints. AFMT appears to be safe and may be effective for gut microbiota restoration in AML patients receiving intensive chemotherapy and antibiotics, with an excellent gut microbiota reconstruction based on both richness and diversity indices at the species level. The combination of chemotherapy and broad-spectrum antibiotics induces gut microbiota (GM) dysbiosis in acute myeloid leukaemia (AML) leading to additional complications. Here, the authors report the efficacy in GM restoration and safety of autologous faecal microbiota transfer in treated AML patients in a phase II clinical trial. [ABSTRACT FROM AUTHOR]

Hypomethylating agents are a classical frontline low-intensity therapy for older patients with acute myeloid leukemia. Recently, TP53 gene mutations have been described as a potential predictive biomarker of better outcome in patients treated with a ten-day decitabine regimen., However, functional characteristics of TP53 mutant are heterogeneous, as reflected in multiple functional TP53 classifications and their impact in patients treated with azacitidine is less clear. We analyzed the therapeutic course and outcome of 279 patients treated with azacitidine between 2007 and 2016, prospectively enrolled in our regional healthcare network. By screening 224 of them, we detected TP53 mutations in 55 patients (24.6%), including 53 patients (96.4%) harboring high-risk cytogenetics. The identification of any TP53 mutation was associated with worse overall survival but not with response to azacitidine in the whole cohort and in the subgroup of patients with adverse karyotype. Stratification of patients according to three recent validated functional classifications did not allow the identification of TP53 mutated patients who could benefit from azacitidine. Systematic TP53 mutant classification will deserve further exploration in the setting of patients treated with conventional therapy and in the emerging field of therapies targeting TP53 pathway. [ABSTRACT FROM AUTHOR]

Objectives: Complete responses have been observed in NPM1‐mutated AML patients with dactinomycin, a nucleolar stress‐inducing drug. Here, we report a single‐center experience of compassionate use of dactinomycin in untreated or relapsed/ refractory NPM1‐mutated AML. Methods: From September 2015 to February 2019, 26 adult patients with NPM1‐mutated AML received dactinomycin in different situations: front‐line treatment in 4 unfit patients (16%); morphologic (n = 16, 62%), molecular relapses (n = 4, 16%), refractory disease (n = 1, 13%), or postremission therapy in second complete response (n = 1, 13%). Results: Median age was 62.5 years. Median number of dactinomycin cycle was 1 (1‐8), and 7 patients (27%) received more than 3 cycles. Three out of 17 patients (18%) in morphologic relapse or refractory to chemotherapy achieved complete remission after the first cycle of dactinomycin. None of the 4 patients unfit for intensive chemotherapy responded to dactinomycin as front‐line therapy. 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%). Conclusions: Dactinomycin is an inexpensive and easily available drug that may induce significant responses in few AML patients with NPM1 mutations with an acceptable safety profile. [ABSTRACT FROM AUTHOR]

Autophagy has been associated with oncogenesis with one of its emerging key functions being its contribution to the metabolism of tumors. Therefore, deciphering the mechanisms of how autophagy supports tumor cell metabolism is essential. Here, we demonstrate that the inhibition of autophagy induces an accumulation of lipid droplets (LD) due to a decrease in fatty acid β-oxidation, that leads to a reduction of oxidative phosphorylation (OxPHOS) in acute myeloid leukemia (AML), but not in normal cells. Thus, the autophagic process participates in lipid catabolism that supports OxPHOS in AML cells. Interestingly, the inhibition of OxPHOS leads to LD accumulation with the concomitant inhibition of autophagy. Mechanistically, we show that the disruption of mitochondria–endoplasmic reticulum (ER) contact sites (MERCs) phenocopies OxPHOS inhibition. Altogether, our data establish that mitochondria, through the regulation of MERCs, controls autophagy that, in turn finely tunes lipid degradation to fuel OxPHOS supporting proliferation and growth in leukemia. How autophagy supports tumor cell metabolism is not fully clear. Here, the authors show that autophagy regulates lipid availability to support mitochondrial oxidative metabolism through mitochondria-endoplasmic reticulum contact sites, necessary for cell proliferation in AML. [ABSTRACT FROM AUTHOR]

Höllein A et al. examined paired samples of I NPM1 i m AML at diagnosis and relapse and found that I NPM1 i m relapses occurred significantly earlier than I NPM1 i wt relapses (14 I vs i . 43 months) [[14]]. Here, we show that I NPM1 i mutations could be lost in late relapses (4 out of 10 cases), suggesting that these late relapses originate from a clonal evolution, with the persistence of preexisting clonal hematopoiesis predisposing to relapse, or from the emergence of a novel AML secondary to the treatment of the first one, or both. In our series, among the four late relapses with loss of I NPM1 i mutations, two acquired monosomy 7 at relapse suggesting that these apparent relapses were likely therapy-related AML. [Extracted from the article]

We recently identified the CDC25A phosphatase as a key actor in proliferation and differentiation in acute myeloid leukemia expressing the FLT3-ITD mutation. In this paper we demonstrate that CDC25A level is controlled by a complex STAT5/miR-16 transcription and translation pathway working downstream of this receptor. First, we established by CHIP analysis that STAT5 is directly involved in FLT3-ITD-dependent CDC25A gene transcription. In addition, we determined that miR-16 expression is repressed by FLT3-ITD activity, and that STAT5 participates in this repression. In accordance with these results, miR-16 expression was significantly reduced in a panel of AML primary samples carrying the FLT3-ITD mutation when compared with FLT3wt cells. The expression of a miR-16 mimic reduced CDC25A protein and mRNA levels, and RNA interference-mediated down modulation of miR-16 restored CDC25A expression in response to FLT3-ITD inhibition. Finally, decreasing miR-16 expression partially restored the proliferation of cells treated with the FLT3 inhibitor AC220, while the expression of miR-16 mimic stopped this proliferation and induced monocytic differentiation of AML cells. In summary, we identified a FLT3-ITD/STAT5/miR-16/CDC25A axis essential for AML cell proliferation and differentiation. [ABSTRACT FROM AUTHOR]

Somatic mutations of isocitrate dehydrogenase 1 ( I IDH1 SP R132 sp i ) genes are found in 6-10% of AML [[1]]. Most patients ( I n i = 42, 85.7%) received induction chemotherapy as first line treatment whereas 3, 3 and 1 patients were treated by hypomethylating agents, best supportive care or other treatment, respectively. Out of the 39 patients who achieved CR/CRi including the three refractory patients that achieved CR/CRi after salvage, 19 relapsed (48.7%) (Supplementary Table S3). [Extracted from the article]

A recent phase 3 trial showed that outcome of older patients with secondary acute myeloid leukemia (AML) may be improved by a liposomal encapsulation of cytarabine and daunorubicin (CPX‐351). This phase 3 study represents a unique example of prospective data in this rare subgroup providing basis for comparison with real life data. Here, we retrospectively assessed characteristics and outcome of patients aged 60‐75 years with secondary or therapy‐related AML in real life. Out of 218 patients that fulfilled CPX‐351 study criteria, 181 patients (83.0%) received antileukemic treatment either intensive chemotherapy (n = 121) or hypomethylating agents (HMA, n = 60). As compared with patients treated by chemotherapy, HMA‐treated patients were older, had lower WBC, more often AML with antecedent myelodysplastic syndrome and adverse cytogenetic risk. In chemotherapy‐treated patients, the complete response rate was 69%, median overall survival (OS) was 11 months whereas 3‐year and 5‐year OS was 21% and 17%, respectively. In HMA‐treated patients, the complete response rate was 15%, median OS was 11 months whereas 3‐year and 5‐year OS was 15% and 2%, respectively. In conclusion, although outcome of older patients with high‐risk AML is very poor, a significant proportion of patients treated by standard intensive chemotherapy but not HMA are long‐term survivors. [ABSTRACT FROM AUTHOR]

Objectives: 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. [ABSTRACT FROM AUTHOR]

The article presents a study which assessed the outcome of the relapsed or refractory acute myeloid leukemia (R/R AML) treated with more intensive regimen used in routine practice. Topics discussed include characteristics of patients treated with intensive salvage chemotherapy at the time of failure or relapse, main factors that discriminate R/R AML patients selected for phase 3 trials, and one of the main flaws of the phase 3 trial.

Résumé Le traitement des leucémies aiguës myéloïdes (LAM) reste un challenge, en particulier dans certains sous-groupes où la chimiothérapie conventionnelle, peu modifiée depuis 40 ans, n’apporte que peu de bénéfice. La découverte d’anomalies génétiques récurrentes a permis d’approfondir la connaissance de cette maladie hétérogène, mais aussi de stimuler la recherche fondamentale et clinique. Un long et minutieux travail d’amélioration du schéma d’administration des deux drogues phares (anthracyclines et cytarabine), des tentatives d’association à une troisième molécule et la recherche de thérapies ciblées efficaces sont les trois grandes lignes des nouvelles approches thérapeutiques dans les LAM. Des alternatives à la chimiothérapie voient le jour, mais il reste à savoir qui peut en bénéficier. Enfin, l’ère de l’immunothérapie va peut-être changer la prise en charge des LAM comme cela se dessine dans les leucémies aiguës lymphoblastiques. Comment améliorer le classique « 3+7 » ? Quelles sont les molécules prometteuses dans le traitement des LAM ? Voici un tour d’horizon des nouvelles approches thérapeutiques dans les LAM. Summary Acute myeloid leukemia (AML) treatment still remains a challenge, in particular in some subgroups, where conventional chemotherapy (fewly modified for 40 years) appears to be disappointing. The discovery of recurring genetic abnormalities has permitted to go thoroughly into the knowledge of this heterogeneous disease, and to stimulate fundamental and clinical research. A long and meticulous work to improve the administration scheme of the two key drugs (anthracyclines and cytarabine), third drug association attempts and search for efficacious targeted therapy are the three main lines of action of the new therapeutic approaches in AML. Alternatives to chemotherapy are being developed, but who they will benefit to remains to be clarified. Lastly, immunotherapy era may have begun in AML as it is the case in acute lymphoblastic leukemia. How can we improve the classical « 3+7 »? Which are the promising molecules in AML treatment? Here is an overview of the new therapeutic approaches in AML. [ABSTRACT FROM AUTHOR]

The absolute lymphocyte count (ALC) at presentation has been associated with survival in various malignancies. However, its prognostic value in acute myeloid leukemia (AML) has not been established. In a series of 1702 newly diagnosed patients with AML, we evaluated the prognostic value of ALC at diagnosis with regard to induction chemotherapy response, disease-free survival (DFS) and overall survival (OS). Low initial ALC (< 1 × 109/L) appeared as a poor prognostic factor for DFS ( p = 0.01) and OS ( p = 0.02), while higher ALC (> 4.5 × 109/L) showed a lower response rate after one ( p = 0.004) or two induction chemotherapy courses ( p = 0.01). However, ALC did not appear as an independent predictor of outcome in a multivariate analysis model also including age, cytogenetics and white blood cell count. Examination of lymphocyte subsets is warranted to specify the relationship between ALC at diagnosis and clinical outcome in AML. [ABSTRACT FROM AUTHOR]

The authors discuss the development of the diagnosis and treatment of acute myeloid leukemia (AML). Topics include the potential of gene mutation in terms of prognosis, therapeutic options for AML such as intensive conventional chemotherapy and application of genetically driven strategies or genetically targeted therapies. Also examined is the impact of time from diagnosis to treatment initiation on patient outcome.

Simple Summary: Around 15% of acute myeloid leukemia (AML) patients harbor mutations in isocitrate dehydrogenases (IDH), which lead to the production of the oncometabolite 2-hydroxyglutarate (2-HG). Inhibitors of mutant IDH enzymes and their 2-HG production have been approved by the FDA to be used in patients. However, 60% of IDH mutant AML patients do not respond to these inhibitors or develop mechanisms of resistance, leading to relapse. Among these mechanisms, some produce a 2-HG rebound. Alternative therapies exploiting the 2-HG-dependent molecular effects could therefore be of clinical interest. In this study, we demonstrate that 2-HG specifically activates vitamin D receptor (VDR) in IDH mutant AML cells leading to increased sensitivity to the combination of vitamin D (or VDR agonist) and all-trans retinoic acid and revealing a new therapeutic approach that can be readily applied to AML patients in this subgroup. Relapses and resistance to therapeutic agents are major barriers in the treatment of acute myeloid leukemia (AML) patients. These unfavorable outcomes emphasize the need for new strategies targeting drug-resistant cells. As IDH mutations are present in the preleukemic stem cells and systematically conserved at relapse, targeting IDH mutant cells could be essential to achieve a long-term remission in the IDH mutant AML subgroup. Here, using a panel of human AML cell lines and primary AML patient specimens harboring IDH mutations, we showed that the production of an oncometabolite (R)-2-HG by IDH mutant enzymes induces vitamin D receptor-related transcriptional changes, priming these AML cells to differentiate with pharmacological doses of ATRA and/or VD. This activation occurs in a CEBPα-dependent manner. Accordingly, our findings illuminate potent and cooperative effects of IDH mutations and the vitamin D receptor pathway on differentiation in AML, revealing a novel therapeutic approach easily transferable/immediately applicable to this subgroup of AML patients. [ABSTRACT FROM AUTHOR]

Two recent phase 3 trials showed that outcomes for relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) patients may be improved by a single-agent tyrosine kinase inhibitor (TKI) (i.e., quizartinib or gilteritinib). In the current study, we retrospectively investigated the characteristics and real-world outcomes of R/R FLT3-internal tandem duplication (ITD) acute myeloid leukemia (AML) patients in the Toulouse-Bordeaux DATAML registry. In the study, we included 316 patients with FLT3-ITD AML that received intensive chemotherapy as a first-line treatment. The rate of complete remission (CR) or CR without hematological recovery (CRi) was 75.2%, and 160 patients were R/R after a first-line TKI-free treatment (n = 294). Within the subgroup of R/R patients that fulfilled the main criteria of the QUANTUM-R study, 48.9% received an intensive salvage regimen; none received hypomethylating agents or low-dose cytarabine. Among the R/R FLT3-ITD AML patients with CR1 durations < 6 months who received intensive TKI-free treatment, the rate of CR or CRi after salvage chemotherapy was 52.8%, and these results allowed a bridge to be transplanted in 39.6% of cases. Finally, in this QUANTUM-R standard arm-matched cohort, the median overall survival (OS) was 7.0 months and 1-, 3- and 5-year OS were 30.2%, 23.7% and 21.4%, respectively. To conclude, these real-world data show that the intensity of the second-line treatment likely affects response and transplantation rates. Furthermore, the results indicate that including patients with low-intensity regimens, such as low-dose cytarabine or hypomethylating agents, in the control arm of a phase 3 trial may be counterproductive and could compromise the results of the study. [ABSTRACT FROM AUTHOR]

The prognostic impact of immunophenotypic CD34+CD38−CD123+ leukemic stem cell (iLSC) frequency at diagnosis has been demonstrated in younger patients treated by intensive chemotherapy, however, this is less clear in older patients. Furthermore, the impact of iLSC in patients treated by hypomethylating agents is unknown. In this single-center study, we prospectively assessed the CD34+CD38−CD123+ iLSC frequency at diagnosis in acute myeloid leukemia (AML) patients aged 60 years or older. In a cohort of 444 patients, the median percentage of iLSC at diagnosis was 4.3%. Significant differences were found between treatment groups with a lower median in the intensive chemotherapy group (0.6%) compared to hypomethylating agents (8.0%) or supportive care (11.1%) (p <0.0001). In the intensive chemotherapy group, the median overall survival was 34.5 months in patients with iLSC ≤0.10% and 14.6 months in patients with >0.10% (p = 0.031). In the multivariate analyses of this group, iLSC frequency was significantly and independently associated with the incidence of relapse, event-free, relapse-free, and overall survival. However, iLSC frequency had no prognostic impact on patients treated by hypomethylating agents. Thus, the iLSC frequency at diagnosis is an independent prognostic factor in older acute myeloid patients treated by intensive chemotherapy but not hypomethylating agents. [ABSTRACT FROM AUTHOR]

A recent phase 3 trial showed that the outcome of patients with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) improved with gilteritinib, a single-agent second-generation FLT3 tyrosine kinase inhibitor (TKI), compared with standard of care. In this trial, the response rate with standard therapy was particularly low. We retrospectively assessed the characteristics and outcome of patients with R/R FLT3-mutated AML included in the Toulouse–Bordeaux DATAML registry. Among 347 patients who received FLT3 TKI-free intensive chemotherapy as first-line treatment, 174 patients were refractory (n = 48, 27.6%) or relapsed (n = 126, 72.4%). Salvage treatments consisted of intensive chemotherapy (n = 99, 56.9%), azacitidine or low-dose cytarabine (n = 9, 5.1%), other low-intensity treatments (n = 17, 9.8%), immediate allogeneic stem cell transplantation (n = 4, 2.3%) or best supportive care only (n = 45, 25.9%). Among the 114 patients who previously received FLT3 TKI-free intensive chemotherapy as first-line treatment (refractory, n = 32, 28.1%; relapsed, n = 82, 71.9%), the rate of CR (complete remission) or CRi (complete remission with incomplete hematologic recovery) after high- or low-intensity salvage treatment was 50.0%, with a bridge to transplant in 34.2% (n = 39) of cases. The median overall survival (OS) was 8.2 months (interquartile range, 3.0–32); 1-, 3- and 5-year OS rates were 36.0% (95%CI: 27–45), 24.7% (95%CI: 1–33) and 19.7% (95%CI: 1–28), respectively. In this real-word study, although response rate appeared higher than the controlled arm of the ADMIRAL trial, the outcome of patients with R/R FLT3-mutated AML remains very poor with standard salvage therapy. [ABSTRACT FROM AUTHOR]

• Outcome of AML patients with IDH2 R172 mutations is favorable with a median OS of 41 months. • Half of R/R AML patients with IDH2 mutations can achieve CR with conventional treatments. • Median OS of refractory or first-relapsed IDH2mut AML patients is 15 months. Describing the prognosis of sub-groups of acute myeloid leukemia (AML) patients treated in real world with current therapies is becoming increasingly relevant to estimate the benefit that new targeted drugs will bring in the field. This is particularly the case when novel drugs are registered on the basis of non-randomized studies. IDH2 inhibitors have recently emerged as promising drugs in patients with IDH2 R140 or IDH2 R172 mutations. Enasidenib, a first-in-class IDH2 inhibitor, has been approved following promising results of a phase 1–2 clinical trial in relapsed or refractory AML patients with IDH2 mutations. In this study, we described the characteristics, treatments and outcome of 75 IDH2 mutated patients both at diagnosis and relapse or refractory disease. Among the 33 relapsed/refractory AML patients with either IDH2 R140 or IDH2 R172, 28 (84.8%) patients received salvage therapy and 14 achieved a complete response (50%). Median duration of response was 15.2 months. Median, 1-y, 3-y and 5-y OS were 15.1 months (IQR, 4.6–37.7), 53.1% (95% CI, 33.2–69.5), 29.2% (95% CI, 12.6–48.1) and 24.4% (95% CI, 9.3–43.1), respectively. In responding patients, median OS was 37.7 months and 1-y, 3-y and 5-y OS was 85.7%, 57.1% and 47.6%, respectively. In non-responding patients, median OS was 5.0 months (IQR, 4.5–8.6) and 1-y and 3-y OS was 17.9% and 0%, respectively. Thus, a substantial number of R/R AML patients with IDH2 mutations can be salvaged by current treatments and benefit from prolonged survival. It is expected that novel targeted agents such as enasidenib will further improve efficacy and safety in the next future. [ABSTRACT FROM AUTHOR]

The prognostic value of ferritin level at diagnosis in AML patients is unknown. We studied 162 younger AML patients with intermediate-risk cytogenetics who received intensive chemotherapy. The median ferritin level at diagnosis was 633 μg/L and 128 (79%) patients had a ferritin level above the upper normal limit. Hyperferritinemia was significantly associated with a higher cumulative incidence of relapse as well as poorer disease-free and overall survival. In multivariate analysis, hyperferritinemia remained an independent poor prognosis factor. The level of ferritin at diagnosis has a major impact on relapse suggesting a link between inflammation, oxidative stress and chemoresistance in AML. [ABSTRACT FROM AUTHOR]

Although core-binding factor-acute myeloid leukemia (CBF-AML) (t[8;21] or inv[16]/ t[16;16]) represents a favorable cytogenetic AML subgroup, 30% to 40% of these patients relapse after standard intensive chemotherapy. The encouraging results of gemtuzumab ozogamicin (GO) in newly diagnosed AML, and particularly in CBF-AML, incited us to retrospectively investigate the impact of GO-based salvage in these patients. We retrospectively analyzed the outcome of 145 patients with CBF-AML (591[8;21], 86 inv[16]/t[16;16]) in first relapse. As salvage, 48 patients received GO-based chemotherapy and 97 patients received conventional chemotherapy. Median age was 43 years (range, 16-76). Median first complete remission duration was 12.1 months (range, 2.1-93.6). Overall, second complete remission (CR2) rate was 88%. With a median follow-up from relapse of 3.5 years, the estimated 5-year disease-free survival (DFS) was 50% and 5-year overall survival (OS) was 51 %. Older age and shorter first complete remission duration was associated with a shorter OS. Patients treated with GO had similar CR2 rate but significantly higher 5-year DFS (68% vs 42%; P = .05) and OS (65% vs 44%; P = .02). In multivariate analysis, GO salvage was still associated with a significant benefit in DFS and OS. In the 78 patients who received allogeneic hematopoietic stem cell transplantation in CR2, GO before transplant significantly improved posttransplant DFS and OS without excess of treatment-related mortality. (Blood. 2014;124(8):1312-1319) [ABSTRACT FROM AUTHOR]

We designed artificial intelligence-based prediction models (AIPM) using 52 diagnostic variables from 3687 patients included in the DATAML registry treated with intensive chemotherapy (IC, N = 3030) or azacitidine (AZA, N = 657) for an acute myeloid leukemia (AML). A neural network called multilayer perceptron (MLP) achieved a prediction accuracy for overall survival (OS) of 68.5% and 62.1% in the IC and AZA cohorts, respectively. The Boruta algorithm could select the most important variables for prediction without decreasing accuracy. Thirteen features were retained with this algorithm in the IC cohort: age, cytogenetic risk, white blood cells count, LDH, platelet count, albumin, MPO expression, mean corpuscular volume, CD117 expression, NPM1 mutation, AML status (de novo or secondary), multilineage dysplasia and ASXL1 mutation; and 7 variables in the AZA cohort: blood blasts, serum ferritin, CD56, LDH, hemoglobin, CD13 and disseminated intravascular coagulation (DIC). We believe that AIPM could help hematologists to deal with the huge amount of data available at diagnosis, enabling them to have an OS estimation and guide their treatment choice. Our registry-based AIPM could offer a large real-life dataset with original and exhaustive features and select a low number of diagnostic features with an equivalent accuracy of prediction, more appropriate to routine practice. [Display omitted] • We designed AIPM for AML OS prediction with real-life data from the DATAML database. • We compared various techniques of machine learning and applied the Boruta algorithm. • We were able to select the most important diagnostic variables for OS prediction. • AIPM can help hematologists to deal with the amount of data available at diagnosis. • AIPM can help hematologists to have an OS estimation for treatment choice. [ABSTRACT FROM AUTHOR]

Platelet transfusion refractoriness (PTR) is a major adverse event in the management of acute myeloid leukemia (AML). In a series of 897 adult patients with AML receiving intensive chemotherapy, we identified 41 patients (4.8%) with PTR. PTR was more frequently observed in parous women, patients with extra-medullary disease, a low white blood cell count, an infection, or hemophagocytic syndrome. Among the 31 patients with anti-human leucocyte antigen (HLA) antibodies, an HLA-matched donor was identified for 18 patients (58.1%). Median time between diagnosis of PTR and the first HLA-matched transfusion was 12.5 days. HLA-matched transfusions induced a significant increment in platelet counts in 37% of cases. Thrombopoietin receptor agonists were given to 10 patients but did not shorten the duration of thrombocytopenia, reduce severe bleeding, or early death. Grade 3 − 4 bleeding events during induction, early death caused by bleeding, and death caused by bleeding at any time were significantly greater in patients that had platelet transfusion refractoriness (22% vs . 4.1%, P < 0.0001; 12.2% vs . 1.4%, P = 0.0006; and 24.4% vs . 5.3%, P < 0.0001; respectively). PTR during chemotherapy for AML significantly increased the risk of early and late deaths caused by a severe bleeding event. Improved understanding of platelet destruction is needed to design mechanism-based therapeutic strategies. [ABSTRACT FROM AUTHOR]